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Chen C, Ji Y, Liu H, Pang L, Chen J, Chen H, Yao Y, Ye J, Wang S, Liu S, Zhong Y. Acid sphingomyelinase downregulation alleviates diabetic myocardial fibrosis in mice. Mol Cell Biochem 2025; 480:3749-3763. [PMID: 39853662 DOI: 10.1007/s11010-025-05206-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 01/04/2025] [Indexed: 01/26/2025]
Abstract
Increased activity of acid sphingomyelinase (ASMase) has been linked to diabetes and organ fibrosis. Nevertheless, the precise influence of ASMase on diabetic myocardial fibrosis and the corresponding molecular mechanisms remain elusive. In this study, we aim to elucidate whether ASMase contributes to diabetic myocardial fibrosis through the phosphorylation mediated by MAPK, thereby culminating in the development of diabetic cardiomyopathy (DCM). In vitro experiments utilized cardiac fibroblasts (CFs) isolated from wild-type mice (WT). For in vivo studies, ASMase knockout mice were generated through TALEN gene editing technology. Additionally, a diabetes mellitus model was established by intraperitoneal injection of Streptozotocin (STZ), involving both ASMase knockdown mice (ASMase+/--STZ) and WT mice. CFs were subjected to incubation with amitriptyline (AMP) (2.5 μM), advanced glycation end products (AGEs), and small interfering RNA (siRNA) over a duration of 24 h. Experimental assessments encompassed EdU incorporation, transwell assays, and fluorescence staining, aimed at elucidating the functional characteristics of cardiac fibroblasts. The quantification of collagen I, phosphorylated MAPK levels within both cellular and murine cardiac contexts was accomplished through Western blot analysis. In the ASMase±-STZ group, mice exhibited attenuated myocardial fibrosis and ameliorated cardiac diastolic function in comparison to the WT-STZ group. Furthermore, treatment of CFs with AMP and siRNA demonstrated a suppressive effect on the proliferation and fibrotic expression induced by AGEs in CFs. Our investigation unveiled that ASMase modulates myocardial fibrosis through the TGF-β-Smad3 and MAPK pathways, elucidating the intricate molecular mechanisms underlying the observed effects. Our findings indicate that ASMase plays a vital role in myocardial fibrosis in DCM, providing a foundation for developing new therapeutic strategies for the prevention and control of DCM.
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Affiliation(s)
- Changnong Chen
- Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory, Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China.
| | - Yang Ji
- Department of Emergency, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Hao Liu
- Department of Anaesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Lihua Pang
- Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory, Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Jing Chen
- Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory, Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Huanzhen Chen
- Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory, Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Yujie Yao
- Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Jinhao Ye
- Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory, Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Sha Wang
- Department of Emergency, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Shiming Liu
- Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory, Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Yun Zhong
- Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory, Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
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Paulik KA, Ivanics T, Dunay GA, Fülöp Á, Kerék M, Takács K, Benyó Z, Miklós Z. Inhibition of the Renin-Angiotensin System Improves Hemodynamic Function of the Diabetic Rat Heart by Restoring Intracellular Calcium Regulation. Biomedicines 2025; 13:757. [PMID: 40149735 PMCID: PMC11940043 DOI: 10.3390/biomedicines13030757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/04/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Disrupted intracellular calcium (Ca2+i) regulation and renin-angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: Experiments were conducted on T1D and T2D Sprague-Dawley rats induced by streptozotocin and fructose-rich diet, respectively. In T1D, rats were treated with Enalapril (Ena) or Losartan (Los) for six weeks, whereas T2D animals received high-dose (HD) or low-dose (LD) Ena for 8 weeks. Heart function was assessed via echocardiography, Ca2+i transients by Indo-1 fluorometry in Langendorff-perfused hearts, and key Ca2+i cycling proteins by Western blot. Data: mean ± SD. Results: Diabetic hearts exhibited reduced contractile performance that was improved by RAS inhibition both in vivo (ejection fraction (%): T1D model: Control: 79 ± 7, T1D: 54 ± 11, T1D + Ena: 65 ± 10, T1D + Los: 69 ± 10, n = 18, 18, 15, 10; T2D model: Control: 73 ± 8, T2D: 52 ± 6, T2D + LDEna: 62 ± 8, T2D + HDEna: 76 ± 8, n = 9, 8, 6, 7) and ex vivo (+dPressure/dtmax (mmHg/s): T1D model: Control: 2532 ± 341, T1D: 2192 ± 208, T1D + Ena: 2523 ± 485, T1D + Los: 2643 ± 455; T2D model: Control: 2514 ± 197, T2D: 1930 ± 291, T2D + LDEna: 2311 ± 289, T2D + HDEna: 2614 ± 268). Analysis of Ca2+i transients showed impaired Ca2+i release and removal dynamics and increased diastolic Ca2+i levels in both models that were restored by Ena and Los treatments. We observed a decrease in sarcoendoplasmic reticulum Ca2+-ATPase2a (SERCA2a) expression, accompanied by a compensatory increase in 16Ser-phosphorylated phospholamban (P-PLB) in T2D that was prevented by both LD and HD Ena (expression level (% of Control): SERCA2a: T2D: 36 ± 32, T2D + LDEna: 112 ± 32, T2D + HDEna: 106 ± 30; P-PLB: T2D: 557 ± 156, T2D + LDEna: 129 ± 38, T2D + HDEna: 108 ± 42; n = 4, 4, 4). Conclusions: The study highlights the critical role of RAS activation, most likely occurring at the tissue level, in disrupting Ca2+i homeostasis in diabetic cardiomyopathy. RAS inhibition with Ena or Los mitigates these disturbances independent of blood pressure effects, underlining their importance in managing diabetic heart failure.
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Affiliation(s)
- Krisztina Anna Paulik
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
| | - Tamás Ivanics
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
| | - Gábor A. Dunay
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
- Klinikum Westbrandenburg, Brandenburg Medical School (MHB), 14770 Brandenburg an der Havel, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senfteberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, 14476 Potsdam, Germany
| | - Ágnes Fülöp
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
- HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, 1094 Budapest, Hungary
| | - Margit Kerék
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
| | - Klára Takács
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
- HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, 1094 Budapest, Hungary
| | - Zsuzsanna Miklós
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (K.A.P.); (T.I.); (G.A.D.); (Á.F.); (K.T.); (Z.B.)
- National Korányi Institute for Pulmonology, 1122 Budapest, Hungary
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Polson SM, Thornburg JP, McNair BD, Cook CZ, Straight EA, Fontana KC, Hoopes CR, Nair S, Bruns DR. Right ventricular dysfunction in preclinical models of type I and type II diabetes. Can J Physiol Pharmacol 2025; 103:86-97. [PMID: 39693609 DOI: 10.1139/cjpp-2024-0195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
Diabetic cardiomyopathy (DCM) is a growing clinical entity and major health burden characterized by comorbid diabetes mellitus and heart failure. DCM has been commonly associated with impaired function of the left ventricle (LV); however, DCM likely also occurs in the right ventricle (RV) which has distinct physiology and pathophysiology from the LV. RV dysfunction is the strongest determinant of mortality in several clinical contexts yet remains poorly studied in diabetes. We investigated RV-specific pathophysiology using two models of diabetes-a well-characterized type 2 diabetes (T2DM) model of high-fat diet and low-dose streptozotocin (STZ) in the mouse and a large animal model of type I diabetes in domestic pigs rendered diabetic with STZ. RV global and systolic function deteriorated with diabetes, alongside hypertrophic and fibrotic remodeling. We report evidence of impaired RV insulin sensitivity, dysregulated RV metabolic gene expression, and impaired mitochondrial dynamics. Importantly, while some of these outcomes were similar to those widely reported in the LV, others were not, such as unchanged antioxidant gene expression and regulators of fatty acid uptake. Importantly, these RV-specific changes occurred in both male and female T2DM mice, together emphasizing the importance of distinguishing the RV from the LV when studying DCM and begging the consideration of RV-specific therapies.
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MESH Headings
- Animals
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/physiopathology
- Diabetes Mellitus, Type 2/metabolism
- Male
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 1/metabolism
- Female
- Ventricular Dysfunction, Right/physiopathology
- Ventricular Dysfunction, Right/metabolism
- Ventricular Dysfunction, Right/etiology
- Ventricular Dysfunction, Right/complications
- Mice
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Experimental/metabolism
- Disease Models, Animal
- Diabetic Cardiomyopathies/physiopathology
- Diabetic Cardiomyopathies/metabolism
- Heart Ventricles/physiopathology
- Heart Ventricles/metabolism
- Mice, Inbred C57BL
- Swine
- Diet, High-Fat/adverse effects
- Insulin Resistance
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Affiliation(s)
- Sydney M Polson
- Kinesiology & Health, University of Wyoming, Laramie, WY, USA
| | | | | | | | | | - Kevin C Fontana
- Kinesiology & Health, University of Wyoming, Laramie, WY, USA
| | - Caleb R Hoopes
- WWAMI Medical Education, University of Washington, Seattle, WA, USA
| | - Sreejayan Nair
- WWAMI Medical Education, University of Washington, Seattle, WA, USA
- School of Pharmacy, University of Wyoming, Laramie, WY, USA
| | - Danielle R Bruns
- Kinesiology & Health, University of Wyoming, Laramie, WY, USA
- WWAMI Medical Education, University of Washington, Seattle, WA, USA
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Ju IJ, Tsai BCK, Kuo WW, Kuo CH, Lin YM, Hsieh DJY, Pai PY, Huang SE, Lu SY, Lee SD, Huang CY. Rhodiola and Salidroside Attenuate Oxidative Stress-Triggered H9c2 Cardiomyoblast Apoptosis Through IGF1R-Induced ERK1/2 Activation. ENVIRONMENTAL TOXICOLOGY 2024; 39:5150-5161. [PMID: 39109685 DOI: 10.1002/tox.24372] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/15/2024] [Accepted: 06/08/2024] [Indexed: 10/17/2024]
Abstract
Oxidative stress is a pivotal factor in the pathogenesis of various cardiovascular diseases. Rhodiola, a traditional Chinese medicine, is recognized for its potent antioxidant properties. Salidroside, a phenylpropanoid glycoside derived from Rhodiola rosea, has shown remarkable antioxidant capabilities. This study aimed to elucidate the potential protective mechanisms of Rhodiola and salidroside against H2O2-induced cardiac apoptosis in H9c2 cardiomyoblast cells. H9c2 cells were exposed to H2O2 for 4 h, and subsequently treated with Rhodiola or salidroside for 24 h. Cell viability and apoptotic pathways were assessed. The involvement of insulin-like growth factor 1 receptor (IGF1R) and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) were investigated. H2O2 (100 μM) exposure significantly induced cardiac apoptosis in H9c2 cells. However, treatment with Rhodiola (12.5, 25, and 50 μg/mL) and salidroside (0.1, 1, and 10 nM) effectively attenuated H2O2-induced cytotoxicity and apoptosis. This protective effect was associated with IGF1R-activated phosphorylation of ERK1/2, leading to the inhibition of Fas-dependent proteins, HIF-1α, Bax, and Bak expression in H9c2 cells. The images from hematoxylin and eosin staining and immunofluorescence assays also revealed the protective effects of Rhodiola and salidroside in H9c2 cells against oxidative damage. Our findings suggest that Rhodiola and salidroside possess antioxidative properties that mitigate H2O2-induced apoptosis in H9c2 cells. The protective mechanisms involve the activation of IGF1R and subsequent phosphorylation of ERK1/2. These results propose Rhodiola and salidroside as potential therapeutic agents for cardiomyocyte cytotoxicity and apoptosis induced by oxidative stress in heart diseases. Future studies may explore their clinical applications in cardiac health.
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Affiliation(s)
- I-Ju Ju
- Division of General Medicine, Department of Medical Education, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Bruce Chi-Kang Tsai
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
- Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, Taiwan
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
- Institute of Sports Sciences, University of Taipei, Taipei, Taiwan
- Department of Kinesiology and Health Science, College of William and Mary, Williamsburg, VA, USA
- School of Physical Education and Sports Science, Soochow University, Suzhou, Jiangsu, China
| | - Yueh-Min Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Dennis Jine-Yuan Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Pei-Ying Pai
- Division of Cardiovascular Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Shang-En Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Shang-Yeh Lu
- Division of Cardiovascular Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Shin-Da Lee
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Rehabilitation Medicine, Weifang Medical University, Weifang, Shandong, China
- Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
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5
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Lee WS, Abel ED, Kim J. New Insights into IGF-1 Signaling in the Heart. Physiology (Bethesda) 2024; 39:0. [PMID: 38713091 DOI: 10.1152/physiol.00003.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 04/24/2024] [Accepted: 05/04/2024] [Indexed: 05/08/2024] Open
Abstract
Insulin-like growth factor-1 (IGF-1) signaling has multiple physiological roles in cellular growth, metabolism, and aging. Myocardial hypertrophy, cell death, senescence, fibrosis, and electrical remodeling are hallmarks of various heart diseases and contribute to the progression of heart failure. This review highlights the critical role of IGF-1 and its cognate receptor in cardiac hypertrophy, aging, and remodeling.
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Affiliation(s)
- Wang-Soo Lee
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - E Dale Abel
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
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6
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Zhong J, Lin X, Zheng X, Zhou Y, Huang H, Xu L. Diminished levels of insulin-like growth factor-1 may be a risk factor for peripheral neuropathy in type 2 diabetes patients. J Diabetes Investig 2024; 15:1259-1265. [PMID: 38923403 PMCID: PMC11363116 DOI: 10.1111/jdi.14260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 06/03/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
AIMS/INTRODUCTION To investigate risk factors for diabetic peripheral neuropathy (DPN) and to explore the connection between insulin-like growth factor-1 (IGF-1) and DPN in individuals with type 2 diabetes. MATERIALS AND METHODS A total of 790 patients with type 2 diabetes participated in a cross-sectional study, divided into two groups: those with DPN (DPN) and those without DPN (non-DPN). Blood samples were taken to measure IGF-1 levels and other biochemical markers. Participants underwent nerve conduction studies and quantitative sensory testing. RESULTS Patients with DPN exhibited significantly lower levels of IGF-1 compared with non-DPN patients (P < 0.001). IGF-1 was positively correlated with the average amplitude of both motor (P < 0.05) and sensory nerves (P < 0.05), but negatively correlated with the vibration perception threshold (P < 0.05). No significant difference was observed between IGF-1 and nerve conduction velocity (P > 0.05), or the temperature detection threshold (P > 0.05). Multivariate regression analysis identified diabetes duration, HbA1c, and the low levels of IGF-1 as independent risk factors (P < 0.001). Receiver operating characteristic analysis determined that at 8 years duration of diabetes, 8.5% (69.4 mmol/mol) HbA1c and 120 ng/mL IGF-1, the optimal cut-off points, indicated DPN (P < 0.001). CONCLUSIONS A reduction of IGF-1 in patients with DPN suggests a potential protective role against axon injury in large fiber nerves of type 2 diabetes patients.
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Affiliation(s)
- Jingyi Zhong
- Department of Endocrinology, Shenzhen HospitalSouthern Medical UniversityShenzhenGuangdongChina
- The Third School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Xiaopu Lin
- Department of Huiqiao Medical Centre, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Xiaobin Zheng
- Department of Endocrinology, Shenzhen HospitalSouthern Medical UniversityShenzhenGuangdongChina
- The Third School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Yanting Zhou
- Department of Endocrinology, Shenzhen HospitalSouthern Medical UniversityShenzhenGuangdongChina
- The Third School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Haishan Huang
- Department of Endocrinology, Shenzhen HospitalSouthern Medical UniversityShenzhenGuangdongChina
- The Third School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Lingling Xu
- Department of Endocrinology, Shenzhen HospitalSouthern Medical UniversityShenzhenGuangdongChina
- The Third School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
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7
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Chen Y, Wijekoon S, Matsumoto A, Luo J, Kiriazis H, Masterman E, Yildiz G, Cross J, Parslow A, Chooi R, Sadoshima J, Greening D, Weeks K, McMullen J. Distinct functional and molecular profiles between physiological and pathological atrial enlargement offer potential new therapeutic opportunities for atrial fibrillation. Clin Sci (Lond) 2024; 138:941-962. [PMID: 39018488 PMCID: PMC11292366 DOI: 10.1042/cs20240178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 07/17/2024] [Accepted: 07/17/2024] [Indexed: 07/19/2024]
Abstract
Atrial fibrillation (AF) remains challenging to prevent and treat. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to AF. Atrial enlargement in response to physiological stimuli such as exercise is typically benign and reversible. Understanding the differences in atrial function and molecular profile underpinning pathological and physiological atrial remodelling will be critical for identifying new strategies for AF. The discovery of molecular mechanisms responsible for pathological and physiological ventricular hypertrophy has uncovered new drug targets for heart failure. Studies in the atria have been limited in comparison. Here, we characterised mouse atria from (1) a pathological model (cardiomyocyte-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and (2) a physiological model (cardiomyocyte-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Both models presented with an increase in atrial mass, but displayed distinct functional, cellular, histological and molecular phenotypes. Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Atrial proteomics identified protein networks related to cardiac contractility, sarcomere assembly, metabolism, mitochondria, and extracellular matrix which were differentially regulated in the models; many co-identified in atrial proteomics data sets from human AF. In summary, physiological and pathological atrial enlargement are associated with distinct features, and the proteomic dataset provides a resource to study potential new regulators of atrial biology and function, drug targets and biomarkers for AF.
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MESH Headings
- Atrial Fibrillation/physiopathology
- Atrial Fibrillation/metabolism
- Atrial Fibrillation/genetics
- Animals
- Heart Atria/metabolism
- Heart Atria/physiopathology
- Heart Atria/pathology
- Mice, Transgenic
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Atrial Remodeling
- Receptor, IGF Type 1/metabolism
- Receptor, IGF Type 1/genetics
- Cardiomyopathy, Dilated/physiopathology
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/metabolism
- Cardiomyopathy, Dilated/pathology
- Disease Models, Animal
- Fibrosis
- Mice
- Humans
- Signal Transduction
- Phosphatidylinositol 3-Kinases/metabolism
- Heart Failure/physiopathology
- Heart Failure/genetics
- Heart Failure/metabolism
- Heart Failure/pathology
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Affiliation(s)
- Yi Ching Chen
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia
| | - Seka Wijekoon
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Aya Matsumoto
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Jieting Luo
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Emma Masterman
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Gunes Yildiz
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Jonathon Cross
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Adam C. Parslow
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia
| | - Roger Chooi
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, NJ, U.S.A
| | - David W. Greening
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia
| | - Kate L. Weeks
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - Julie R. McMullen
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia
- Monash Alfred Baker Centre for Cardiovascular Research, Monash University, Melbourne, Victoria, Australia
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8
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Adasheva DA, Serebryanaya DV. IGF Signaling in the Heart in Health and Disease. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:1402-1428. [PMID: 39245453 DOI: 10.1134/s0006297924080042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/11/2024] [Accepted: 06/22/2024] [Indexed: 09/10/2024]
Abstract
One of the most vital processes of the body is the cardiovascular system's proper operation. Physiological processes in the heart are regulated by the balance of cardioprotective and pathological mechanisms. The insulin-like growth factor system (IGF system, IGF signaling pathway) plays a pivotal role in regulating growth and development of various cells and tissues. In myocardium, the IGF system provides cardioprotective effects as well as participates in pathological processes. This review summarizes recent data on the role of IGF signaling in cardioprotection and pathogenesis of various cardiovascular diseases, as well as analyzes severity of these effects in various scenarios.
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Affiliation(s)
- Daria A Adasheva
- Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
| | - Daria V Serebryanaya
- Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
- Pirogov Russian National Research Medical University, Moscow, 117997, Russia
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Yao B, Lv J, Du L, Zhang H, Xu Z. Phoenixin-14 protects cardiac damages in a streptozotocin-induced diabetes mice model through SIRT3. Arch Physiol Biochem 2024; 130:110-118. [PMID: 34618648 DOI: 10.1080/13813455.2021.1981946] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/13/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Type I diabetes is a metabolic syndrome that severely impacts the normal lives of patients through its multiple complications, such as diabetic cardiomyopathy (DCM). Phoenixin-14 is a peptide found to be widely expressed in eukaryons with multiple protective properties, including anti-oxidative stress and anti-inflammatory effects. The present study aims to explore the potential therapeutic impacts of Phoenixin-14 on DCM. METHODS Type I diabetes was induced by treatment with a single dose of STZ (40 mg/kg body weight) intraperitoneally for 5 consecutive days. Mice were divided into four groups: the Control, Phoenixin-14, T1DM, and Phoenixin-14 +T1DM groups. The levels of myocardial injury markers were measured. Cardiac hypertrophy was assessed using wheat germ agglutinin (WGA) staining. RESULTS Phoenixin-14 was significantly downregulated in the cardiac tissue of diabetic mice. The myocardial injury and deteriorated cardiac function in diabetic mice induced by STZ were significantly ameliorated by Phoenixin-14, accompanied by the alleviation of cardiac hypertrophy. In addition, the severe oxidative stress and inflammation in diabetic mice were dramatically mitigated by Phoenixin-14. Lastly, the downregulated SIRT3 and upregulated p-FOXO3 in diabetic mice were pronouncedly reversed by Phoenixin-14. It is worth mentioning that compared to the Control, no significant changes to any of the investigated parameters in the present study were found in the Phoenixin-14-treated normal mice, suggesting that treatment with it has no side effects. CONCLUSION Our data revealed that Phoenixin-14 protected against cardiac damages in STZ-induced diabetes mice models.
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Affiliation(s)
- Bo Yao
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Third Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Junlin Lv
- Department of Anesthesiology, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Le Du
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Third Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hui Zhang
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Third Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhao Xu
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Third Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Trotta MC, Herman H, Ciceu A, Mladin B, Rosu M, Lepre CC, Russo M, Bácskay I, Fenyvesi F, Marfella R, Hermenean A, Balta C, D’Amico M. Chrysin-based supramolecular cyclodextrin-calixarene drug delivery system: a novel approach for attenuating cardiac fibrosis in chronic diabetes. Front Pharmacol 2023; 14:1332212. [PMID: 38169923 PMCID: PMC10759242 DOI: 10.3389/fphar.2023.1332212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
Introduction: Cardiac fibrosis is strongly induced by diabetic conditions. Both chrysin (CHR) and calixarene OTX008, a specific inhibitor of galectin 1 (Gal-1), seem able to reduce transforming growth factor beta (TGF-β)/SMAD pro-fibrotic pathways, but their use is limited to their low solubility. Therefore, we formulated a dual-action supramolecular system, combining CHR with sulfobutylated β-cyclodextrin (SBECD) and OTX008 (SBECD + OTX + CHR). Here we aimed to test the anti-fibrotic effects of SBECD + OTX + CHR in hyperglycemic H9c2 cardiomyocytes and in a mouse model of chronic diabetes. Methods: H9c2 cardiomyocytes were exposed to normal (NG, 5.5 mM) or high glucose (HG, 33 mM) for 48 h, then treated with SBECD + OTX + CHR (containing OTX008 0.75-1.25-2.5 µM) or the single compounds for 6 days. TGF-β/SMAD pathways, Mitogen-Activated Protein Kinases (MAPKs) and Gal-1 levels were assayed by Enzyme-Linked Immunosorbent Assays (ELISAs) or Real-Time Quantitative Reverse Transcription Polymerase chain reaction (qRT-PCR). Adult CD1 male mice received a single intraperitoneal (i.p.) administration of streptozotocin (STZ) at a dosage of 102 mg/kg body weight. From the second week of diabetes, mice received 2 times/week the following i.p. treatments: OTX (5 mg/kg)-SBECD; OTX (5 mg/kg)-SBECD-CHR, SBECD-CHR, SBECD. After a 22-week period of diabetes, mice were euthanized and cardiac tissue used for tissue staining, ELISA, qRT-PCR aimed to analyse TGF-β/SMAD, extracellular matrix (ECM) components and Gal-1. Results: In H9c2 cells exposed to HG, SBECD + OTX + CHR significantly ameliorated the damaged morphology and reduced TGF-β1, its receptors (TGFβR1 and TGFβR2), SMAD2/4, MAPKs and Gal-1. Accordingly, these markers were reduced also in cardiac tissue from chronic diabetes, in which an amelioration of cardiac remodeling and ECM was evident. In both settings, SBECD + OTX + CHR was the most effective treatment compared to the other ones. Conclusion: The CHR-based supramolecular SBECD-calixarene drug delivery system, by enhancing the solubility and the bioavailability of both CHR and calixarene OTX008, and by combining their effects, showed a strong anti-fibrotic activity in rat cardiomyocytes and in cardiac tissue from mice with chronic diabetes. Also an improved cardiac tissue remodeling was evident. Therefore, new drug delivery system, which could be considered as a novel putative therapeutic strategy for the treatment of diabetes-induced cardiac fibrosis.
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Affiliation(s)
- Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Hildegard Herman
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Alina Ciceu
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Bianca Mladin
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Marcel Rosu
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Caterina Claudia Lepre
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
- PhD Course in Translational Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Marina Russo
- PhD Course in National Interest in Public Administration and Innovation for Disability and Social Inclusion, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
- School of Pharmacology and Clinical Toxicology, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Ildikó Bácskay
- Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
- Institute of Healthcare Industry, University of Debrecen, Debrecen, Hungary
| | - Ferenc Fenyvesi
- Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Anca Hermenean
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
- Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, Arad, Romania
| | - Cornel Balta
- “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Michele D’Amico
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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Florczyk-Soluch U, Polak K, Sabo R, Martyniak A, Stępniewski J, Dulak J. Compromised diabetic heart function is not affected by miR-378a upregulation upon hyperglycemia. Pharmacol Rep 2023; 75:1556-1570. [PMID: 37851320 PMCID: PMC10661816 DOI: 10.1007/s43440-023-00535-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/19/2023] [Accepted: 09/25/2023] [Indexed: 10/19/2023]
Abstract
BACKGROUND Cardiac-abundant microRNA-378a (miR-378a) is associated with postnatal repression of insulin-like growth factor 1 receptor (IGF-1R) controlling physiological hypertrophy and survival pathways. IGF-1/IGF-1R axis has been proposed as a therapeutic candidate against the pathophysiological progress of diabetic cardiomyopathy (DCM). We ask whether hyperglycemia-driven changes in miR-378a expression could mediate DCM progression. METHODS Diabetes mellitus was induced by streptozotocin (STZ) (55 mg/kg i.p. for 5 days) in male C57BL/6 wild type (miR-378a+/+) and miR-378a knockout (miR-378a-/-) mice. As a parallel human model, we harnessed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM miR378a+/+ vs. hiPSC-CM miR378a-/-) subjected to high glucose (HG) treatment. RESULTS We reported miR-378a upregulation in cardiac diabetic milieu arising upon STZ administration to wild-type mice and in HG-treated hiPSC-CMs. Pro-hypertrophic IGF-1R/ERK1/2 pathway and hypertrophic marker expression were activated in miR-378a deficiency and upon STZ/HG treatment of miR-378a+/+ specimens in vivo and in vitro suggesting miR-378a-independent hyperglycemia-promoted hypertrophy. A synergistic upregulation of IGF-1R signaling in diabetic conditions was detected in miR-378a-/- hiPSC-CMs, but not in miR-378a-/- hearts that showed attenuation of this pathway, pointing to the involvement of compensatory mechanisms in the absence of miR-378a. Although STZ administration did not cause pro-inflammatory or pro-fibrotic effects that were detected in miR-378a-/- mice, the compromised diabetic heart function observed in vivo by high-resolution ultrasound imaging upon STZ treatment was not affected by miR-378a presence. CONCLUSIONS Overall, data underline the role of miR-378a in maintaining basal cardiac structural integrity while pointing to miR-378a-independent hyperglycemia-driven cardiac hypertrophy and associated dysfunction.
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Affiliation(s)
- Urszula Florczyk-Soluch
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.
| | - Katarzyna Polak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Reece Sabo
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Alicja Martyniak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Jacek Stępniewski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
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Yu Y, Yang W, Dai X, Yu L, Lan Z, Ding X, Zhang J. Microvascular Myocardial Ischemia in Patients With Diabetes Without Obstructive Coronary Stenosis and Its Association With Angina. Korean J Radiol 2023; 24:1081-1092. [PMID: 37899519 PMCID: PMC10613843 DOI: 10.3348/kjr.2023.0297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/04/2023] [Accepted: 07/30/2023] [Indexed: 10/31/2023] Open
Abstract
OBJECTIVE To investigate the incidence of microvascular myocardial ischemia in diabetic patients without obstructive coronary artery disease (CAD) and its relationship with angina. MATERIALS AND METHODS Diabetic patients and an intermediate-to-high pretest probability of CAD were prospectively enrolled. Non-diabetic patients but with an intermediate-to-high pretest probability of CAD were retrospectively included as controls. The patients underwent dynamic computed tomography-myocardial perfusion imaging (CT-MPI) and coronary computed tomography angiography (CCTA) to quantify coronary stenosis, myocardial blood flow (MBF), and extracellular volume (ECV). The proportion of patients with microvascular myocardial ischemia, defined as any myocardial segment with a mean MBF ≤ of 100 mL/min/100 mL, in patients without obstructive CAD (Coronary Artery Disease-Reporting and Data System [CAD-RADS] grade 0-2 on CCTA) was determined. Various quantitative parameters of the patients with and without diabetes without obstructive CAD were compared. Multivariable analysis was used to determine the association between microvascular myocardial ischemia and angina symptoms in diabetic patients without obstructive CAD. RESULTS One hundred and fifty-two diabetic patients (mean age: 59.7 ± 10.7; 77 males) and 266 non-diabetic patients (62.0 ± 12.3; 167 males) were enrolled; CCTA revealed 113 and 155 patients without obstructive CAD, respectively. For patients without obstructive CAD, the mean global MBF was significantly lower for those with diabetes than for those without (152.8 mL/min/100 mL vs. 170.4 mL/min/100 mL, P < 0.001). The mean ECV was significantly higher for diabetic patients (27.2% vs. 25.8%, P = 0.009). Among the patients without obstructive CAD, the incidence of microvascular myocardial ischemia (36.3% [41/113] vs. 10.3% [16/155], P < 0.001) and interstitial fibrosis (69.9% [79/113] vs. 33.3% [8/24], P = 0.001) were significantly higher in diabetic patients than in the controls. The presence of microvascular myocardial ischemia was independently associated with angina symptoms (adjusted odds ratio = 3.439, P = 0.037) in diabetic patients but without obstructive CAD. CONCLUSION Dynamic CT-MPI + CCTA revealed a high incidence of microvascular myocardial ischemia in diabetic patients without obstructive CAD. Microvascular myocardial ischemia is strongly associated with angina.
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Affiliation(s)
- Yarong Yu
- Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenli Yang
- Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Dai
- Institute of Diagnostic and Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lihua Yu
- Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziting Lan
- Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoying Ding
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jiayin Zhang
- Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Mouat JS, Li S, Myint SS, Laufer BI, Lupo PJ, Schraw JM, Woodhouse JP, de Smith AJ, LaSalle JM. Epigenomic signature of major congenital heart defects in newborns with Down syndrome. Hum Genomics 2023; 17:92. [PMID: 37803336 PMCID: PMC10559462 DOI: 10.1186/s40246-023-00540-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 10/02/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs. METHODS We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples. RESULTS We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples. CONCLUSIONS A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
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Affiliation(s)
- Julia S Mouat
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA
- Perinatal Origins of Disparities Center, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Shaobo Li
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Swe Swe Myint
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Benjamin I Laufer
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA
- Perinatal Origins of Disparities Center, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Philip J Lupo
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Jeremy M Schraw
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - John P Woodhouse
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Adam J de Smith
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Janine M LaSalle
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
- Perinatal Origins of Disparities Center, University of California, Davis, CA, USA.
- Genome Center, University of California, Davis, CA, USA.
- MIND Institute, University of California, Davis, CA, USA.
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Zhang P, Li H, Zhang A, Wang X, Song Q, Li Z, Wang W, Xu J, Hou Y, Zhang Y. Mechanism of myocardial fibrosis regulation by IGF-1R in atrial fibrillation through the PI3K/Akt/FoxO3a pathway. Biochem Cell Biol 2023; 101:432-442. [PMID: 37018819 DOI: 10.1139/bcb-2022-0199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023] Open
Abstract
Atrial structural remodeling takes on a critical significance to the occurrence and maintenance of atrial fibrillation (AF). As revealed by recent data, insulin-like growth factor-1 receptor (IGF-1R) plays a certain role in tissue fibrosis. In this study, the mechanism of IGF-1R in atrial structural remodeling was examined based on in vivo and in vitro experiments. First, cluster analysis of AF hub genes was conducted, and then the molecular mechanism was proposed by which IGF-1R regulates myocardial fibrosis via the PI3K/Akt/FoxO3a pathway. Subsequently, the mentioned mechanism was verified in human cardiac fibroblasts (HCFs) and rats transduced with IGF-1 overexpression type 9 adeno-associated viruses. The results indicated that IGF-1R activation up-regulated collagen Ⅰ protein expression and Akt phosphorylation in HCFs and rat atrium. The administration of LY294002 reversed the above phenomenon, improved the shortening of atrial effective refractory period, and reduced the increased incidence of AF and atrial fibrosis in rats. The transfection of FoxO3a siRNA reduced the anti-fibrotic effect of LY294002 in HCFs. The above data revealed that activation of IGF-1R takes on a vital significance to atrial structural remodeling by facilitating myocardial fibrosis and expediting the occurrence and maintenance of AF through the regulation of the PI3K/Akt/FoxO3a signaling pathway.
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Affiliation(s)
- Pei Zhang
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. Ji'nan City, Shandong Province, China
| | - Huilin Li
- Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University. Ji'nan City, Shandong Province, China
| | - An Zhang
- Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University. Ji'nan City, Shandong Province, China
| | - Xiao Wang
- Department of Health Management Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. Ji'nan City, Shandong Province, China
| | - Qiyuan Song
- Shandong First Medical University, The First Affiliated Hospital of Shandong First Medical University. Ji'nan City, Shandong Province, China
| | - Zhan Li
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. Ji'nan City, Shandong Province, China
| | - Weizong Wang
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. Ji'nan City, Shandong Province, China
| | - Jingwen Xu
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. Ji'nan City, Shandong Province, China
| | - Yinglong Hou
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. Ji'nan City, Shandong Province, China
| | - Yong Zhang
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. Ji'nan City, Shandong Province, China
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Zhu J, Li Q, Sun Y, Zhang S, Pan R, Xie Y, Chen J, Shi L, Chen Y, Sun Z, Zhang L. Insulin-Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II-Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal-Regulated Kinase/Nuclear Factor-κB Pathway. J Am Heart Assoc 2023; 12:e029631. [PMID: 37721135 PMCID: PMC10547288 DOI: 10.1161/jaha.123.029631] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 08/15/2023] [Indexed: 09/19/2023]
Abstract
Background The renin-angiotensin system plays a crucial role in the development of heart failure, and Ang II (angiotensin II) acts as the critical effector of the renin-angiotensin system in regulating cardiac fibrosis. However, the mechanisms of cardiac fibrosis are complex and still not fully understood. IGF1R (insulin-like growth factor 1 receptor) has multiple functions in maintaining cardiovascular homeostasis, and low-dose IGF1 treatment is effective in relieving Ang II-induced cardiac fibrosis. Here, we aimed to investigate the molecular mechanism of IGF1R in Ang II-induced cardiac fibrosis. Methods and Results Using primary mouse cardiac microvascular endothelial cells and fibroblasts, in vitro experiments were performed. Using C57BL/6J mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)-mediated IGF1R heterozygous knockout (Igf1r+/-) mice, cardiac fibrosis mouse models were induced by Ang II for 2 weeks. The expression of IGF1R was examined by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot. Mice heart histologic changes were evaluated using Masson and picro sirius red staining. Fibrotic markers and signal molecules indicating the function of the Akt (protein kinase B)/ERK (extracellular signal-regulated kinase)/nuclear factor-κB pathway were detected using quantitative reverse transcription polymerase chain reaction and Western blot. RNA sequencing was used to explore IGF1R-mediated target genes in the hearts of mice, and the association of IGF1R and G-protein-coupled receptor kinase 5 was identified by coimmunoprecipitation. More important, blocking IGF1R signaling significantly suppressed endothelial-mesenchymal transition in primary mouse cardiac microvascular endothelial cells and mice in response to transforming growth factor-β1 or Ang II, respectively. Deficiency or inhibition of IGF1R signaling remarkably attenuated Ang II-induced cardiac fibrosis in primary mouse cardiac fibroblasts and mice. We further observed that the patients with heart failure exhibited higher blood levels of IGF1 and IGF1R than healthy individuals. Moreover, Ang II treatment significantly increased cardiac IGF1R in wild type mice but led to a slight downregulation in Igf1r+/- mice. Interestingly, IGF1R deficiency significantly alleviated cardiac fibrosis in Ang II-treated mice. Mechanistically, the phosphorylation level of Akt and ERK was upregulated in Ang II-treated mice, whereas blocking IGF1R signaling in mice inhibited these changes of Akt and ERK phosphorylation. Concurrently, phosphorylated p65 of nuclear factor-κB exhibited similar alterations in the corresponding group of mice. Intriguingly, IGF1R directly interacted with G-protein-coupled receptor kinase 5, and this association decreased ≈50% in Igf1r+/- mice. In addition, Grk5 deletion downregulated expression of the Akt/ERK/nuclear factor-κB signaling pathway in primary mouse cardiac fibroblasts. Conclusions IGF1R signaling deficiency alleviates Ang II-induced cardiac fibrosis, at least partially through inhibiting endothelial-mesenchymal transition via the Akt/ERK/nuclear factor-κB pathway. Interestingly, G-protein-coupled receptor kinase 5 associates with IGF1R signaling directly, and it concurrently acts as an IGF1R downstream effector. This study suggests the promising potential of IGF1R as a therapeutic target for cardiac fibrosis.
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Affiliation(s)
- Jiafeng Zhu
- Department of NursingWeifang Medical UniversityWeifangChina
| | - Qian Li
- Department of NursingWeifang Medical UniversityWeifangChina
| | - Yan Sun
- Department of StomatologyWeifang Medical UniversityWeifangChina
| | - Shiyu Zhang
- Department of NursingWeifang Medical UniversityWeifangChina
| | - Ruiyan Pan
- Department of PharmacologyWeifang Medical UniversityWeifangChina
| | - Yanguang Xie
- Department of NursingWeifang Medical UniversityWeifangChina
| | - Jinyan Chen
- Department of Clinical MedicineWeifang Medical UniversityWeifangChina
| | - Lihong Shi
- Department of Rehabilitation MedicineWeifang Medical UniversityWeifangChina
| | - Yanbo Chen
- Department of Cardiology, The First Affiliated HospitalWeifang Medical UniversityWeifangChina
| | - Zhipeng Sun
- Department of PharmacologyWeifang Medical UniversityWeifangChina
| | - Lane Zhang
- Department of NursingWeifang Medical UniversityWeifangChina
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Mouat JS, Li S, Myint SS, Laufer BI, Lupo PJ, Schraw JM, Woodhouse JP, de Smith AJ, LaSalle JM. Epigenomic signature of major congenital heart defects in newborns with Down syndrome. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.05.02.23289417. [PMID: 37205408 PMCID: PMC10187438 DOI: 10.1101/2023.05.02.23289417] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Background Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS) but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs. Methods We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: 1) 45 DS-CHD (27 female, 18 male) and 2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD vs DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS vs typical development (TD) WGBS NDBS samples. Results We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3,938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS vs TD samples. Conclusions A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
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Affiliation(s)
- Julia S Mouat
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA USA
- Perinatal Origins of Disparities Center, University of California, Davis, CA USA
- Genome Center, University of California, Davis, CA USA
- MIND Institute, University of California, Davis, CA USA
| | - Shaobo Li
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA USA
| | - Swe Swe Myint
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA USA
| | - Benjamin I Laufer
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA USA
- Perinatal Origins of Disparities Center, University of California, Davis, CA USA
- Genome Center, University of California, Davis, CA USA
- MIND Institute, University of California, Davis, CA USA
| | - Philip J Lupo
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
| | - Jeremy M Schraw
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
| | - John P Woodhouse
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
| | - Adam J de Smith
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA USA
| | - Janine M LaSalle
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA USA
- Perinatal Origins of Disparities Center, University of California, Davis, CA USA
- Genome Center, University of California, Davis, CA USA
- MIND Institute, University of California, Davis, CA USA
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17
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Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice. Biomedicines 2023; 11:biomedicines11030662. [PMID: 36979641 PMCID: PMC10045486 DOI: 10.3390/biomedicines11030662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 02/24/2023] Open
Abstract
Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.
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18
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Huang YL, Xiang Q, Zou JJ, Wu Y, Yu R. Zuogui Jiangtang Shuxin formula Ameliorates diabetic cardiomyopathy mice via modulating gut-heart axis. Front Endocrinol (Lausanne) 2023; 14:1106812. [PMID: 36843604 PMCID: PMC9948445 DOI: 10.3389/fendo.2023.1106812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/16/2023] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND There is growing evidence demonstrating that the gut microbiota plays a crucial role in multiple endocrine disorders, including diabetic cardiomyopathy (DCM). Research shows that the Chinese herb reduces disease occurrence by regulating gut microbiota. Zuogui Jiangtang Shuxin formula (ZGJTSXF), a Chinese medicinal formula, has been clinically used for treatment of DCM for many years. However, there is still no clear understanding of how ZGJTSXF treatment contributes to the prevention and treatment of DCM through its interaction with gut microbiota and metabolism. METHODS In this study, mice models of DCM were established, and ZGJTSXF's therapeutic effects were assessed. Specifically, serum glycolipid, echocardiography, histological staining, myocardial apoptosis rate were assessed. Using 16s rRNA sequencing and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), we determined the impact of ZGJTSXF on the structure of gut microbiota and content of its metabolite TMAO. The mechanism of ZGJTSXF action on DCM was analyzed using quantitative real-time PCR and western blots. RESULTS We found that ZGJTSXF significantly ameliorated DCM mice by modulating gut-heart axis: ZGJTSXF administration improved glycolipid levels, heart function, cardiac morphological changes, inhibited cardiomyocytes apoptosis, and regulate the gut microbiota in DCM mice. Specifically, ZGJTSXF treatment reverse the significant changes in the abundance of certain genera closely related to DCM phenotype, including Lactobacillus, Alloprevotella and Alistipes. Furthermore, ZGJTSXF alleviated DCM in mice by blunting TMAO/PERK/FoxO1 signaling pathway genes and proteins. CONCLUSION ZGJTSXF administration could ameliorate DCM mice by remodeling gut microbiota structure, reducing serum TMAO generation and suppressing TMAO/PERK/FoxO1 signaling pathway.
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Affiliation(s)
- Ya-lan Huang
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Graduate School, Hunan University of Chinese Medicine, Changsha, China
| | - Qin Xiang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Jun-ju Zou
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Yongjun Wu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Rong Yu, ; Yongjun Wu,
| | - Rong Yu
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Rong Yu, ; Yongjun Wu,
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19
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Bernardo BC, Yildiz GS, Kiriazis H, Harmawan CA, Tai CMK, Ritchie RH, McMullen JR. In Vivo Inhibition of miR-34a Modestly Limits Cardiac Enlargement and Fibrosis in a Mouse Model with Established Type 1 Diabetes-Induced Cardiomyopathy, but Does Not Improve Diastolic Function. Cells 2022; 11:cells11193117. [PMID: 36231079 PMCID: PMC9563608 DOI: 10.3390/cells11193117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/21/2022] [Accepted: 09/28/2022] [Indexed: 12/02/2022] Open
Abstract
MicroRNA 34a (miR-34a) is elevated in the heart in a setting of cardiac stress or pathology, and we previously reported that inhibition of miR-34a in vivo provided protection in a setting of pressure overload-induced pathological cardiac hypertrophy and dilated cardiomyopathy. Prior work had also shown that circulating or cardiac miR-34a was elevated in a setting of diabetes. However, the therapeutic potential of inhibiting miR-34a in vivo in the diabetic heart had not been assessed. In the current study, type 1 diabetes was induced in adult male mice with 5 daily injections of streptozotocin (STZ). At 8 weeks post-STZ, when mice had established type 1 diabetes and diastolic dysfunction, mice were administered locked nucleic acid (LNA)-antimiR-34a or saline-control with an eight-week follow-up. Cardiac function, cardiac morphology, cardiac fibrosis, capillary density and gene expression were assessed. Diabetic mice presented with high blood glucose, elevated liver and kidney weights, diastolic dysfunction, mild cardiac enlargement, cardiac fibrosis and reduced myocardial capillary density. miR-34a was elevated in the heart of diabetic mice in comparison to non-diabetic mice. Inhibition of miR-34a had no significant effect on diastolic function or atrial enlargement, but had a mild effect on preventing an elevation in cardiac enlargement, fibrosis and ventricular gene expression of B-type natriuretic peptide (BNP) and the anti-angiogenic miRNA (miR-92a). A miR-34a target, vinculin, was inversely correlated with miR-34a expression, but other miR-34a targets were unchanged. In summary, inhibition of miR-34a provided limited protection in a mouse model with established type 1 diabetes-induced cardiomyopathy and failed to improve diastolic function. Given diabetes represents a systemic disorder with numerous miRNAs dysregulated in the diabetic heart, as well as other organs, strategies targeting multiple miRNAs and/or earlier intervention is likely to be required.
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Affiliation(s)
- Bianca C. Bernardo
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC 3800, Australia
- Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia
| | - Gunes S. Yildiz
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC 3010, Australia
| | | | | | - Rebecca H. Ritchie
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Monash Institute of Pharmaceutical Sciences, Monash University, Royal Parade, Parkville, VIC 3052, Australia
| | - Julie R. McMullen
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC 3800, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC 3010, Australia
- Department of Physiology, Monash University, Clayton, VIC 3800, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia
- Correspondence: ; Tel.: +61-3-8532-1194
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20
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Thomas SS, Wu J, Davogustto G, Holliday MW, Eckel-Mahan K, Verzola D, Garibotto G, Hu Z, Mitch WE, Taegtmeyer H. SIRPα Mediates IGF1 Receptor in Cardiomyopathy Induced by Chronic Kidney Disease. Circ Res 2022; 131:207-221. [PMID: 35722884 PMCID: PMC10010047 DOI: 10.1161/circresaha.121.320546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling. METHODS SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes. RESULTS We demonstrate that SIRPα regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRPα was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRPα was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle-specific SIRPα KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle-specific SIRPα KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRPα directly interacted with IGF1R. Next, rSIRPα (recombinant SIRPα) protein was introduced into muscle-specific SIRPα KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRPα in myoblasts and cardiomyocytes impaired pAKT (phosphorylation of AKT) and insulin/IGF1R signaling. Furthermore, myotubes and cardiomyocytes, but not adipocytes treated with high glucose or cardiomyocytes treated with uremic toxins, stimulated secretion of SIRPα in culture media, suggesting these cells are the origin of circulating SIRPα in CKD. Both intracellular and extracellular SIRPα exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling. CONCLUSIONS Myokine SIRPα expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRPα constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.
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Affiliation(s)
- Sandhya S Thomas
- Nephrology Division, Department of Medicine, Michael E. Debakey VA Medical Center, Houston, TX (S.S.T.).,Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)
| | - Jiao Wu
- Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)
| | - Giovanni Davogustto
- Cardiology Division, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (G.D.)
| | - Michael W Holliday
- Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)
| | - Kristin Eckel-Mahan
- Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (K.E.-M.)
| | - Daniela Verzola
- Nephrology Division, Department of Medicine, Università degli Studi di Genova, Genoa, Italy (D.V., G.G.)
| | - Giacomo Garibotto
- Nephrology Division, Department of Medicine, Università degli Studi di Genova, Genoa, Italy (D.V., G.G.)
| | - Zhaoyong Hu
- Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)
| | - William E Mitch
- Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)
| | - Heinrich Taegtmeyer
- Cardiology Division, Department of Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston (H.T.)
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21
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Prakoso D, De Blasio MJ, Tate M, Ritchie RH. Current landscape of preclinical models of diabetic cardiomyopathy. Trends Pharmacol Sci 2022; 43:940-956. [PMID: 35779966 DOI: 10.1016/j.tips.2022.04.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/04/2022] [Accepted: 04/11/2022] [Indexed: 12/01/2022]
Abstract
Patients with diabetes have an increased risk of developing heart failure, preceded by (often asymptomatic) cardiac abnormalities, collectively called diabetic cardiomyopathy (DC). Diabetic heart failure lacks effective treatment, remaining an urgent, unmet clinical need. Although structural and functional characteristics of the diabetic human heart are well defined, clinical studies lack the ability to pinpoint the specific mechanisms responsible for DC. Preclinical animal models represent a vital component for understanding disease aetiology, which is essential for the discovery of new targeted treatments for diabetes-induced heart failure. In this review, we describe the current landscape of preclinical DC models (genetic, pharmacologically induced, and diet-induced models), highlighting their strengths and weaknesses and alignment to features of the human disease. Finally, we provide tools, resources, and recommendations to assist future preclinical translation addressing this knowledge gap.
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Affiliation(s)
- Darnel Prakoso
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Miles J De Blasio
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia
| | - Mitchel Tate
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Rebecca H Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia; Department of Diabetes, Monash University, Clayton, VIC 3800, Australia.
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22
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Yan W, Li Y, Li G, Yin L, Zhang H, Yan S. Differentiation of Adipose Tissue-Derived Stem Cells into Cardiomyocytes: An Overview. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Cardiovascular diseases, including congenital and acquired cardiovascular diseases, impose a severe burden on healthcare systems worldwide. Although bone marrow-derived stem cells (BMSCs) therapy can be an effective therapeutic strategy for the heart disease, relatively low abundance,
difficult accessibility, and small tissue volume hinder the clinical usefulness. Adipose tissue-derived stem cells (ADSCs) show similar potential with BMSCs to differentiate into lineages and tissues, such as smooth muscle cells, endothelial cells, and adipocytes, with attractiveness of obtaining
adipose tissue easily and repeatedly, and a simple separation procedure. We briefly summarize the current understanding of the cardiomyocytes differentiated from ADSCs
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Affiliation(s)
- Wenju Yan
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250100, China
| | - Yan Li
- Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250100, China
| | - Gaiqin Li
- Department of Gastroenterology, Taian City Central Hospital, Taian, Shandong, 271000, China
| | - Luhua Yin
- Department of Vasculocardiology, Taian City Central Hospital, Taian, Shandong, 271000, China
| | - Huanyi Zhang
- Department of Vasculocardiology, Taian City Central Hospital, Taian, Shandong, 271000, China
| | - Suhua Yan
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250100, China
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23
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Viswanatha GL, Shylaja H, Keni R, Nandakumar K, Rajesh S. A systematic review and meta‐analysis on the cardio‐protective activity of naringin based on pre‐clinical evidences. Phytother Res 2022; 36:1064-1092. [DOI: 10.1002/ptr.7368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/15/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022]
Affiliation(s)
| | | | - Raghuvir Keni
- Department of Pharmacology Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education Manipal India
| | - Krishnadas Nandakumar
- Department of Pharmacology Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education Manipal India
| | - Subbanna Rajesh
- Department of Pharmacology Government College of Pharmacy Bangalore India
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24
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Mittal A, Garg R, Bahl A, Khullar M. Molecular Mechanisms and Epigenetic Regulation in Diabetic Cardiomyopathy. Front Cardiovasc Med 2022; 8:725532. [PMID: 34977165 PMCID: PMC8716459 DOI: 10.3389/fcvm.2021.725532] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/15/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus (DM) is an important lifestyle disease. Type 2 diabetes is one of the prime contributors to cardiovascular diseases (CVD) and diabetic cardiomyopathy (DbCM) and leads to increased morbidity and mortality in patients with DM. DbCM is a typical cardiac disease, characterized by cardiac remodeling in the presence of DM and in the absence of other comorbidities such as hypertension, valvular diseases, and coronary artery disease. DbCM is associated with defective cardiac metabolism, altered mitochondrial structure and function, and other physiological and pathophysiological signaling mechanisms such as oxidative stress, inflammation, myocardial apoptosis, and autophagy. Epigenetic modifiers are crucial players in the pathogenesis of DbCM. Thus, it is important to explore the role of epigenetic modifiers or modifications in regulating molecular pathways associated with DbCM. In this review, we have discussed the role of various epigenetic mechanisms such as histone modifications (acetylation and methylation), DNA methylation and non-coding RNAs in modulating molecular pathways involved in the pathophysiology of the DbCM.
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Affiliation(s)
- Anupam Mittal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rajni Garg
- Council of Scientific and Industrial Research - Institute of Microbial Technology, Chandigarh, India
| | - Ajay Bahl
- Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Madhu Khullar
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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25
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Wu X, Zhang T, Lyu P, Chen M, Ni G, Cheng H, Xu G, Li X, Wang L, Shang H. Traditional Chinese Medication Qiliqiangxin Attenuates Diabetic Cardiomyopathy via Activating PPARγ. Front Cardiovasc Med 2021; 8:698056. [PMID: 34336956 PMCID: PMC8322738 DOI: 10.3389/fcvm.2021.698056] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Diabetic cardiomyopathy is the primary complication associated with diabetes mellitus and also is a major cause of death and disability. Limited pharmacological therapies are available for diabetic cardiomyopathy. Qiliqiangxin (QLQX), a Chinese medication, has been proven to be beneficial for heart failure patients. However, the role and the underlying protective mechanisms of QLQX in diabetic cardiomyopathy remain largely unexplored. Methods: Primary neonatal rat cardiomyocytes (NRCMs) were treated with glucose (HG, 40 mM) to establish the hyperglycemia-induced apoptosis model in vitro. Streptozotocin (STZ, 50 mg/kg/day for 5 consecutive days) was intraperitoneally injected into mice to establish the diabetic cardiomyopathy model in vivo. Various analyses including qRT-PCR, western blot, immunofluorescence [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining] histology (hematoxylin-eosin and Masson's trichrome staining), and cardiac function (echocardiography) were performed in these mice. QLQX (0.5 μg/ml in vitro and 0.5 g/kg/day in vivo) was used in this study. Results: QLQX attenuated hyperglycemia-induced cardiomyocyte apoptosis via activating peroxisome proliferation-activated receptor γ (PPARγ). In vivo, QLQX treatment protected mice against STZ-induced cardiac dysfunction and pathological remodeling. Conclusions: QLQX attenuates diabetic cardiomyopathy via activating PPARγ.
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Affiliation(s)
- Xiaodong Wu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ting Zhang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ping Lyu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mengli Chen
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gehui Ni
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huiling Cheng
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guie Xu
- Cardiac Regeneration and Ageing Lab, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Institute of Cardiovascular Sciences, Shanghai University, Shanghai, China
| | - Xinli Li
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lijun Wang
- Cardiac Regeneration and Ageing Lab, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Institute of Cardiovascular Sciences, Shanghai University, Shanghai, China
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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26
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Ock S, Ham W, Kang CW, Kang H, Lee WS, Kim J. IGF-1 protects against angiotensin II-induced cardiac fibrosis by targeting αSMA. Cell Death Dis 2021; 12:688. [PMID: 34244467 PMCID: PMC8270920 DOI: 10.1038/s41419-021-03965-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022]
Abstract
The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.
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MESH Headings
- Actins/metabolism
- Angiotensin II
- Animals
- Cardiomyopathies/chemically induced
- Cardiomyopathies/metabolism
- Cardiomyopathies/pathology
- Cardiomyopathies/prevention & control
- Cell Proliferation
- Cells, Cultured
- Disease Models, Animal
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Fibrosis
- Infusions, Intravenous
- Insulin-Like Growth Factor I/administration & dosage
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Phenylephrine
- Proto-Oncogene Proteins c-akt/metabolism
- Rats
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Signal Transduction
- rho-Associated Kinases/metabolism
- Mice
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Affiliation(s)
- Sangmi Ock
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Woojin Ham
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Chae Won Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Hyun Kang
- Department of Anesthesiology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Wang Soo Lee
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
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27
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Ahmed U, Ashfaq UA, Qasim M, Ahmad I, Ahmad HU, Tariq M, Masoud MS, Khaliq S. Dysregulation of circulating miRNAs promotes the pathogenesis of diabetes-induced cardiomyopathy. PLoS One 2021; 16:e0250773. [PMID: 33909697 PMCID: PMC8081166 DOI: 10.1371/journal.pone.0250773] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetic Cardiomyopathy (DCM) is characterized by myocardial dysfunction caused by diabetes mellitus. After-effects of diabetic cardiomyopathy are far more lethal than non-diabetic cardiomyopathy. More than 300 million people suffer from diabetes and cardiovascular disorder which is expected to be elevated to an alarming figure of 450 million by 2030. Recent studies suggested that miRNA plays important role in the onset of diabetic cardiomyopathy. This study was designed to identify the miRNA that is responsible for the onset of diabetic cardiomyopathy using in silico and in vitro approaches. In this study, to identify the miRNA responsible for the onset of diabetic cardiomyopathy, in silico analysis was done to predict the role of these circulating miRNAs in type 2 diabetic cardiomyopathy. Shared miRNAs that are present in both diseases were selected for further analysis. Total RNA and miRNA were extracted from blood samples taken from type 2 diabetic patients as well as healthy controls to analyze the expression of important genes like AKT, VEGF, IGF, FGF1, ANGPT2 using Real-time PCR. The expression of ANGPT2 was up-regulated and AKT, VEGF, IGF, FGF1 were down-regulated in DCM patients as compared to healthy controls. The miRNA expression of miR-17 was up-regulated and miR-24, miR-150, miR-199a, miR-214, and miR-320a were down-regulated in the DCM patients as compared to healthy controls. This shows that dysregulation of target genes and miRNA may contribute towards the pathogenesis of DCM and more studies should be conducted to elucidate the role of circulating miRNAs to use them as therapeutic and diagnostic options.
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Affiliation(s)
- Uzair Ahmed
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
- Department of Physiology and Cell Biology, University of Health Sciences, Lahore, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Muhammad Qasim
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Imtiaz Ahmad
- Department of Cardiology, Punjab Institute of Cardiology, Lahore, Pakistan
| | - Hafiz Usman Ahmad
- Department of Physiology and Cell Biology, University of Health Sciences, Lahore, Pakistan
| | - Muhammad Tariq
- Department of Biotechnology, Mirpur University of Sciences and Technology, Mirpur, AJK, Pakistan
| | - Muhammad Shareef Masoud
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Saba Khaliq
- Department of Physiology and Cell Biology, University of Health Sciences, Lahore, Pakistan
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28
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Yin H, Favreau-Lessard AJ, deKay JT, Herrmann YR, Robich MP, Koza RA, Prudovsky I, Sawyer DB, Ryzhov S. Protective role of ErbB3 signaling in myeloid cells during adaptation to cardiac pressure overload. J Mol Cell Cardiol 2020; 152:1-16. [PMID: 33259856 DOI: 10.1016/j.yjmcc.2020.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 11/06/2020] [Accepted: 11/23/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND Myeloid cells play an important role in a wide variety of cardiovascular disorders, including both ischemic and non-ischemic cardiomyopathies. Neuregulin-1 (NRG-1)/ErbB signaling has recently emerged as an important factor contributing to the control of inflammatory activation of myeloid cells after an ischemic injury. However, the role of ErbB signaling in myeloid cells in non-ischemic cardiomyopathy is not fully understood. This study investigated the role of ErbB3 receptors in the regulation of early adaptive response using a mouse model of transverse aortic constriction (TAC) for non-ischemic cardiomyopathy. METHODS AND RESULTS TAC surgery was performed in groups of age- and sex-matched myeloid cell-specific ErbB3-deficient mice (ErbB3MyeKO) and control animals (ErbB3MyeWT). The number of cardiac CD45 immune cells, CD11b myeloid cells, Ly6G neutrophils, and Ly6C monocytes was determined using flow cytometric analysis. Five days after TAC, survival was dramatically reduced in male but not female ErbB3MyeKO mice or control animals. The examination of lung weight to body weight ratio suggested that acute pulmonary edema was present in ErbB3MyeKO male mice after TAC. To determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3MyeKO male mice, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. Myeloid cells accumulated in control but not in ErbB3MyeKO male mouse hearts. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and fibroblasts) in control but not ErbB3MyeKO male mice. No significant differences in intramyocardial accumulation of myeloid cells or proliferation of Sca-1 cells were found between the groups of ErbB3MyeKO and ErbB3MyeWT female mice. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3MyeKO mice hearts compared to control animals after TAC. CONCLUSION Our data demonstrate the crucial role of myeloid cell-specific ErbB3 signaling in the cardiac accumulation of myeloid cells, which contributes to the activation of cardiac endothelial cells and fibroblasts and development of an early adaptive response to cardiac pressure overload in male mice.
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Affiliation(s)
- Haifeng Yin
- Maine Medical Center Research Institute, Scarborough, ME, United States of America
| | | | - Joanne T deKay
- Maine Medical Center Research Institute, Scarborough, ME, United States of America
| | - Yodit R Herrmann
- Maine Medical Center Research Institute, Scarborough, ME, United States of America
| | - Michael P Robich
- Maine Medical Center Research Institute, Scarborough, ME, United States of America; Maine Medical Center, Cardiovascular Institute, Portland, ME, United States of America
| | - Robert A Koza
- Maine Medical Center Research Institute, Scarborough, ME, United States of America
| | - Igor Prudovsky
- Maine Medical Center Research Institute, Scarborough, ME, United States of America
| | - Douglas B Sawyer
- Maine Medical Center Research Institute, Scarborough, ME, United States of America; Maine Medical Center, Cardiovascular Institute, Portland, ME, United States of America
| | - Sergey Ryzhov
- Maine Medical Center Research Institute, Scarborough, ME, United States of America.
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29
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Li G, Yang L, Feng L, Yang J, Li Y, An J, Li D, Xu Y, Gao Y, Li J, Liu J, Yang L, Qi Z. Syringaresinol Protects against Type 1 Diabetic Cardiomyopathy by Alleviating Inflammation Responses, Cardiac Fibrosis, and Oxidative Stress. Mol Nutr Food Res 2020; 64:e2000231. [PMID: 32729956 DOI: 10.1002/mnfr.202000231] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/03/2020] [Indexed: 12/18/2022]
Abstract
SCOPE Syringaresinol (SYR) is a phenolic compound, which could be found in various cereals and medicinal plants. It exerts both anti-inflammatory and antioxidant pharmacological properties. However, little is known about the effect of SYR on modulating diabetic cardiomyopathy. The present study aimed to investigate the pharmacodynamic effect of SYR on diabetic cardiomyopathy and the underlying molecular mechanism. METHODS AND RESULTS In STZ-induced type 1 diabetic mice, orally administration with SYR in every other day for 8 weeks significantly improves cardiac dysfunction and preventes cardiac hypertrophy and fibrosis. The macrophage infiltration and oxidative stress biomarkers are also suppressed by SYR without affecting hyperglycemia and body weight. In neonatal cardiomyocytes, high glucose-induced cell apoptosis and fibrosis are potently decreased by SYR, and the inflammatory response and oxidant stress are also alleviated by SYR incubation. Mechanistically, SYR may exert protective effects by restoring suppression of antioxidant kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-E2-related factor 2 (Nrf2) system and abnormal activation of transforming growth factor-β (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway in vitro and in vivo. CONCLUSION The results indicated that SYR could be a potential therapeutic agent for the treatment of diabetic cardiomyopathy by inhibiting inflammation, fibrosis, and oxidative stress. The signaling pathway of Keap1/Nrf2 and TGF-β/Smad could be used as therapeutic targets for diabetic complications.
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Affiliation(s)
- Guangru Li
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Lei Yang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, 300100, China
| | - Lifeng Feng
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jiu Yang
- Clinical laboratory, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300197, China
| | - Yafei Li
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jiale An
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Dihua Li
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, 300100, China
| | - Yang Xu
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yang Gao
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jing Li
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jie Liu
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Liang Yang
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Zhi Qi
- Department of Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
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30
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Ye Y, Birnbaum Y, Widen SG, Zhang Z, Zhu S, Bajaj M, Chen H. Acupuncture Reduces Hypertrophy and Cardiac Fibrosis, and Improves Heart Function in Mice with Diabetic Cardiomyopathy. Cardiovasc Drugs Ther 2020; 34:835-848. [PMID: 32767170 DOI: 10.1007/s10557-020-07043-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/20/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE To assess the effects of electro-acupuncture (EA) on glycemic control, myocardial inflammation, and the progression of diabetic cardiomyopathy in mice with type 2 diabetes. METHODS Db/Db mice received EA at PC6+ST36 (DM-Acu), non-acupoint simulation (DM-Sham), or no treatment (DM). EA was applied for 30 min per day, 5 days a week for 4 weeks. Heart function was assessed by echocardiography. Myocardium was assessed by RT-PCR, immunoblotting, and histology. Serum TNF-α, IL-1α, IL-1β, IL-6, and IL-8 were measured. RESULTS DM-Acu, but not DM-Sham, reduced fasting blood glucose without affecting body weight. DM decreased systolic function. DM-Acu, but not DM-Sham, attenuated the decrease in systolic function. Heart weight was significantly smaller in the DM-Acu than in the DM and DM-Sham groups. Percent fibrosis and apoptosis were reduced in the DM-Acu, but not the DM-Sham, group. Serum levels of IL-1α, IL-1β, IL-6, IL-8, ICAM-1, MCP-1, and TNF-α were significantly lower in the DM-Acu than in the DM or DM-Sham groups. Protein levels of P-Akt and P-AMPK and mRNA levels of phosphoinositide-3-kinase regulatory subunit 6 (PIK3r6) were significantly higher in the DM-Acu group. Myocardial mRNA and protein levels of insulin-like growth factor 1 receptor (IGF1R) were significantly lower in the DM and DM-Sham groups compared with the DM-Acu group. CONCLUSIONS EA reduced serum glucose; prevented DM-induced hypertrophy and deterioration of systolic function, inflammation, and fibrosis; and restored IGF1R, P-Akt, and P-AMPK levels in mice with type 2 diabetes mellitus.
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Affiliation(s)
- Yumei Ye
- The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Yochai Birnbaum
- The Section of Cardiology, Department of Medicine, Baylor College of Medicine, One Baylor Plaza MS, BCM620, Houston, TX, USA.
| | - Steven G Widen
- The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Zhaohui Zhang
- Department of Acupuncture, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shipeng Zhu
- Second Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mandeep Bajaj
- Section of Endocrinology, Baylor College of Medicine, Houston, TX, USA
| | - Huan Chen
- The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA. .,Department of Acupuncture, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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31
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Lay IS, Kuo WW, Shibu MA, Ho TJ, Cheng SM, Day CH, Ban B, Wang S, Li Q, Huang CY. Exercise training restores IGFIR survival signaling in d-galactose induced-aging rats to suppress cardiac apoptosis. J Adv Res 2020; 28:35-41. [PMID: 33364043 PMCID: PMC7753223 DOI: 10.1016/j.jare.2020.06.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/26/2020] [Accepted: 06/17/2020] [Indexed: 12/18/2022] Open
Abstract
Introduction Insulin-like growth factor-I receptor (IGF1R) mediated survival signaling is a crucial mechanism for cellular endurance and a potential indicator of recuperation in deteriorating hearts. Objective This study evaluates the impact of long-term exercise training in enhancing cardiac survival mechanism in D-galactose-induced toxicity associated aging rats. Methods Forty-eight male SD-rats were segregated into 4 groups (n=9) and were named as control, exercise training groups, aging group and aging group with exercise training. Aging was induced by intraperitoneal (IP) D-galactose (150 mL/kg) injection for 8 weeks and for exercise training, the rats were left to swim in warm water for 60 min every day and 5 times/week. Western blotting of proteins from the left ventricles was performed to identify the modulations in the survival signaling. Tissue sections were analyzed to determine the extent of fibrosis and apoptosis. Results Western-blot analysis performed on the excised left ventricles (LV) showed that proteins of the cardiac survival pathway including IGF1R and Akt and the pro-survival Bcl-2 showed significant decrease in the aging group, whereas the levels were restored in the aging rats subjected to exercise training. In addition, aging groups showed increased interstitial space and collagen accumulation. Further, TUNEL assay showed higher number of apoptotic cells in the LV of aging group, which was correlated with increase in the proteins involved in FAS-FADD-dependent apoptosis. However, these aging associated effects were ameliorated upon exercise training in the D-galactose-induced aging rats that showed elevated IGF1R/Akt signaling. Conclusion The results suggest that IGFIR survival signaling cascadeis elevated in following long-term exercise training and thereby provide cardio-protective benefits in D-galactose induced aging rats.
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Affiliation(s)
- Ing-Shiow Lay
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, 40402 Taichung, Taiwan.,Department of Chinese Medicine, China Medical University Beigang Hospital, Yunlin County 65152, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan
| | - Marthandam Asokan Shibu
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Tsung-Jung Ho
- Integration Center of Traditional Chinese and Modern Medicine, HualienTzu Chi Hospital, Hualien 97002, Taiwan.,Department of Chinese Medicine,Hualien Tzu Chi Hospital, Hualien 97002, Taiwan.,School of Post Baccalaureate Chinese Medicine, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan
| | - Shiu-Min Cheng
- Department of Psychology, Asia University, Taichung, Taiwan
| | | | - Bo Ban
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, Shandong 272029, China
| | - Shulin Wang
- Department of Cardiology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, Guangdong, China
| | - Qiaowen Li
- Department of Cardiology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, Guangdong, China
| | - Chih-Yang Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, 40402 Taichung, Taiwan.,Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan.,Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,Holistic Education Center, Tzu Chi University of Science and Technology, Hualien, Taiwan
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32
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Waldman M, Arad M, Abraham NG, Hochhauser E. The Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1α-Heme Oxygenase 1 Axis, a Powerful Antioxidative Pathway with Potential to Attenuate Diabetic Cardiomyopathy. Antioxid Redox Signal 2020; 32:1273-1290. [PMID: 32027164 PMCID: PMC7232636 DOI: 10.1089/ars.2019.7989] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
Significance: From studies of diabetic animal models, the downregulation of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)-heme oxygenase 1 (HO-1) axis appears to be a crucial event in the development of obesity and diabetic cardiomyopathy (DCM). In this review, we discuss the role of metabolic and biochemical stressors in the rodent and human pathophysiology of DCM. A crucial contributor for many cardiac pathologies is excessive production of reactive oxygen species (ROS) pathologies, which lead to extensive cellular damage by impairing mitochondrial function and directly oxidizing DNA, proteins, and lipid membranes. We discuss the role of ROS production and inflammatory pathways with multiple contributing and confounding factors leading to DCM. Recent Advances: The relevant biochemical pathways that are critical to a therapeutic approach to treat DCM, specifically caloric restriction and its relation to the PGC-1α-HO-1 axis in the attenuation of DCM, are elucidated. Critical Issues: The increased prevalence of diabetes mellitus type 2, a major contributor to unique cardiomyopathy characterized by cardiomyocyte hypertrophy with no effective clinical treatment. This review highlights the role of mitochondrial dysfunction in the development of DCM and potential oxidative targets to attenuate oxidative stress and attenuate DCM. Future Directions: Targeting the PGC-1α-HO-1 axis is a promising approach to ameliorate DCM through improvement in mitochondrial function and antioxidant defenses. A pharmacological inducer to activate PGC-1α and HO-1 described in this review may be a promising therapeutic approach in the clinical setting.
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Affiliation(s)
- Maayan Waldman
- Cardiac Research Laboratory, Felsenstein Medical Research Institute at Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
- Cardiac Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel
| | - Michael Arad
- Cardiac Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel
| | - Nader G. Abraham
- Department of Pharmacology, New York Medical College, Valhalla, New York, USA
| | - Edith Hochhauser
- Cardiac Research Laboratory, Felsenstein Medical Research Institute at Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
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Abstract
Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.
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Affiliation(s)
- Rebecca H. Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia
| | - E. Dale Abel
- Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
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Jin L, Zhang J, Deng Z, Liu J, Han W, Chen G, Si Y, Ye P. Mesenchymal stem cells ameliorate myocardial fibrosis in diabetic cardiomyopathy via the secretion of prostaglandin E2. Stem Cell Res Ther 2020; 11:122. [PMID: 32183879 PMCID: PMC7079514 DOI: 10.1186/s13287-020-01633-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 02/03/2020] [Accepted: 03/04/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Diabetic cardiomyopathy (DCM) is a cardiac complication of long-term uncontrolled diabetes and is characterized by myocardial fibrosis and abnormal cardiac function. Mesenchymal stem cells (MSCs) are multipotent cells with immunoregulatory and secretory functions in diabetes and heart diseases. However, very few studies have focused on the effect and the underlying mechanism of MSCs on myocardial fibrosis in DCM. Therefore, we aimed to explore the therapeutic potential of MSCs in myocardial fibrosis and its underlying mechanism in vivo and in vitro. METHODS A DCM rat model was induced using a high-fat diet (HFD) combined with a low-dose streptozotocin (STZ) injection. After four infusions of MSCs, rat serum and heart tissues were collected, and the levels of blood glucose and lipid, cardiac structure, and function, and the degree of myocardial fibrosis including the expression levels of pro-fibrotic factor and collagen were analyzed using biochemical methods, echocardiography, histopathology, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA). We infused prostaglandin E2 (PGE2)-deficient MSCs to DCM rats in vivo and established a system mimicking diabetic myocardial fibrosis in vitro by inducing cardiac fibroblasts with high glucose (HG) and coculturing them with MSCs or PGE2-deficient MSCs to further explore the underlying mechanism of amelioration of myocardial fibrosis by MSCs. RESULTS Metabolic abnormalities, myocardial fibrosis, and cardiac dysfunction in DCM rats were significantly ameliorated after treatment with MSCs. Moreover, the levels of TGF-β, collagen I, collagen III, and collagen accumulation were markedly decreased after MSC infusion compared to those in DCM hearts. However, PGE2-deficient MSCs had decreased ability to alleviate cardiac fibrosis and dysfunction. In addition, in vitro study revealed that the concentration of PGE2 in the MSC group was enhanced, while the proliferation and collagen secretion of cardiac fibroblasts were reduced after MSC treatment. However, MSCs had little effect on alleviating fibrosis when the fibroblasts were pretreated with cyclooxygenase-2 (COX-2) inhibitors, which also inhibited PGE2 secretion. This phenomenon could be reversed by adding PGE2. CONCLUSIONS Our results indicated that MSC infusion could ameliorate cardiac fibrosis and dysfunction in DCM rats. The underlying mechanisms might involve the function of PGE2 secreted by MSCs.
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Affiliation(s)
- Liyuan Jin
- Department of Geriatric Cardiology, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853 China
- Chinese People’s Liberation Army Medical School, No. 28 Fuxing Road, Beijing, 100853 China
| | - Jinying Zhang
- Chinese People’s Liberation Army Medical School, No. 28 Fuxing Road, Beijing, 100853 China
| | - Zihui Deng
- Chinese People’s Liberation Army Medical School, No. 28 Fuxing Road, Beijing, 100853 China
| | - Jiejie Liu
- Department of Basic Research, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853 China
| | - Weidong Han
- Department of Basic Research, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853 China
| | - Guanghui Chen
- Department of Cardiology, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853 China
| | - Yiling Si
- Department of Basic Research, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853 China
| | - Ping Ye
- Department of Geriatric Cardiology, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853 China
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35
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Krog S, Ludvigsen TP, Nielsen OL, Kirk RK, Lykkegaard K, Wulff EM, Møller JE, Pedersen HD, Olsen LH. Myocardial Changes in Diabetic and Nondiabetic Nonhuman Primates. Vet Pathol 2020; 57:332-343. [PMID: 32096447 DOI: 10.1177/0300985820901332] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Diabetic human patients have increased risk of heart failure compared to healthy subjects. The underlying mechanisms for this are not fully understood, and to help develop improved treatment strategies, well-characterized animal models are essential. To investigate cardiac dysfunction in diabetes, this study evaluated myocardial changes in 10 aging rhesus monkeys with and without diabetes. Based on evaluation of plasma glycosylated hemoglobin and glucose, 7 of 10 rhesus macaques had diabetes for a minimum of 11 months, while 3 of 10 were categorized as nondiabetic. A detailed histological examination of formalin-fixed left ventricular myocardial samples was followed by a semiquantitative evaluation of myocardial fibrosis and fat infiltration; digital quantifications of myocardial collagen, lipofuscin, and nuclear area fractions; and measurements of cardiomyocyte diameter. Histological myocardial evaluation revealed the presence of lipofuscin; large nuclei; interstitial, replacement, and vascular fibrosis; adipocyte infiltration; and vacuolar degeneration with atrophy of cardiomyocytes and fibrosis. However, there were no differences between groups for semiquantitative fat infiltration, fibrosis, cardiomyocyte size, collagen, or nuclear and lipofuscin area fraction. Lipofuscin area fraction correlated with plasma insulin, triglyceride, total cholesterol, and high-density lipoprotein cholesterol concentrations. In conclusion, myocardial pathological changes were found in left ventricular myocardium in aged rhesus macaques, independent of the stage of diabetes. The duration of diabetes might have been too short to cause differences between groups.
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Affiliation(s)
- Simone Krog
- Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | | | - Ole L Nielsen
- Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Rikke K Kirk
- Novo Nordisk A/S, Global Drug Discovery, Måløv, Denmark
| | | | - Erik M Wulff
- Novo Nordisk A/S, Global Drug Discovery, Måløv, Denmark
| | - Jacob E Møller
- Department of Cardiology, Odense University Hospital, Odense, Denmark
| | - Henrik D Pedersen
- Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark.,Ellegaard Göttingen Minipigs A/S, Dalmose, Denmark
| | - Lisbeth H Olsen
- Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
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De Blasio MJ, Huynh N, Deo M, Dubrana LE, Walsh J, Willis A, Prakoso D, Kiriazis H, Donner DG, Chatham JC, Ritchie RH. Defining the Progression of Diabetic Cardiomyopathy in a Mouse Model of Type 1 Diabetes. Front Physiol 2020; 11:124. [PMID: 32153425 PMCID: PMC7045054 DOI: 10.3389/fphys.2020.00124] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 02/04/2020] [Indexed: 12/13/2022] Open
Abstract
The incidence of diabetes and its association with increased cardiovascular disease risk represents a major health issue worldwide. Diabetes-induced hyperglycemia is implicated as a central driver of responses in the diabetic heart such as cardiomyocyte hypertrophy, fibrosis, and oxidative stress, termed diabetic cardiomyopathy. The onset of these responses in the setting of diabetes has not been studied to date. This study aimed to determine the time course of development of diabetic cardiomyopathy in a model of type 1 diabetes (T1D) in vivo. Diabetes was induced in 6-week-old male FVB/N mice via streptozotocin (55 mg/kg i.p. for 5 days; controls received citrate vehicle). At 2, 4, 8, 12, and 16 weeks of untreated diabetes, left ventricular (LV) function was assessed by echocardiography before post-mortem quantification of markers of LV cardiomyocyte hypertrophy, collagen deposition, DNA fragmentation, and changes in components of the hexosamine biosynthesis pathway (HBP) were assessed. Blood glucose and HbA1c levels were elevated by 2 weeks of diabetes. LV and muscle (gastrocnemius) weights were reduced from 8 weeks, whereas liver and kidney weights were increased from 2 and 4 weeks of diabetes, respectively. LV diastolic function declined with diabetes progression, demonstrated by a reduction in E/A ratio from 4 weeks of diabetes, and an increase in peak A-wave amplitude, deceleration time, and isovolumic relaxation time (IVRT) from 4–8 weeks of diabetes. Systemic and local inflammation (TNFα, IL-1β, CD68) were increased with diabetes. The cardiomyocyte hypertrophic marker Nppa was increased from 8 weeks of diabetes while β-myosin heavy chain was increased earlier, from 2 weeks of diabetes. LV fibrosis (picrosirius red; Ctgf and Tgf-β gene expression) and DNA fragmentation (a marker of cardiomyocyte apoptosis) increased with diabetes progression. LV Nox2 and Cd36 expression were elevated after 16 weeks of diabetes. Markers of the LV HBP (Ogt, Oga, Gfat1/2 gene expression), and protein abundance of OGT and total O-GlcNAcylation, were increased by 16 weeks of diabetes. This is the first study to define the progression of cardiac markers contributing to the development of diabetic cardiomyopathy in a mouse model of T1D, confirming multiple pathways contribute to disease progression at various time points.
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Affiliation(s)
- Miles J De Blasio
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,School of BioSciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Nguyen Huynh
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia
| | - Minh Deo
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Leslie E Dubrana
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Jesse Walsh
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Andrew Willis
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Darnel Prakoso
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,School of BioSciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Helen Kiriazis
- Experimental Cardiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Daniel G Donner
- Experimental Cardiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - John C Chatham
- Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Rebecca H Ritchie
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia.,Department of Medicine, Monash University, Melbourne, VIC, Australia.,Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
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The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice. Int J Mol Sci 2020; 21:ijms21041384. [PMID: 32085666 PMCID: PMC7073122 DOI: 10.3390/ijms21041384] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/14/2020] [Accepted: 02/16/2020] [Indexed: 12/11/2022] Open
Abstract
The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1/2 activation in human-engineered FPR-expressing cells, including ERK1/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.
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Xie R, Liu Z, Lin Z, Shi P, Chen B, Li S, Li G, Huang L, Lin X, Yao H. Potential mechanism of action of Ixeris sonchifolia extract injection against cardiovascular diseases revealed by combination of HPLC-Q-TOF-MS, virtual screening and systems pharmacology approach. RSC Adv 2020; 10:38497-38504. [PMID: 35517561 PMCID: PMC9057262 DOI: 10.1039/d0ra07038f] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022] Open
Abstract
Ixeris sonchifolia extract injection, a Chinese medicine preparation named as Kudiezi injection (KDZI) in China, has been widely used for the treatment of cardiovascular diseases (CVDs) in recent years. Owing to the component complexity of the preparation, the study on the effect mechanism of the herbal medicine against CVDs is a big challenge. In this research, HPLC-Q-TOF-MS was used to analyze the constituents of the preparation, disclosing that the KDZI mainly consists of 10 ingredients, namely 3-caffeoylquinic acid (KDZI-1), 4-caffeoylquinic acid (KDZI-2), 5-caffeoylquinic acid (KDZI-3), apigenin-7-O-β-d-glucuronide (KDZI-4), caffeic acid (KDZI-5), chicoric acid (KDZI-6), caftaric acid (KDZI-7), luteolin-7-O-β-d-gentiobioside (KDZI-8), luteolin-7-O-β-d-glucopyranoside (KDZI-9) and luteolin-7-O-β-d-glucuronide (KDZI-10). Afterwards, target fishing and an integrated systems pharmacology approach combined with molecular docking (Sybyl 1.3 and AutoDock Vina) were adopted to predict the potential targets and pathways for the main ingredients in KDZI. As results, 39 protein targets and 9 KEGG pathways, possessing high relevance to the therapeutic effects of the ingredients of KDZI against CVDs, were screened out reasonably. The integrated pharmacology analysis suggested that KDZI could exert its therapeutic effects against CVDs possibly via multi-targets including EGFR, MAPK10, and SRC and multi-pathways referring to MAPK, focal adhesion, complement and coagulation cascades, etc. This research provides insights into understanding the comprehensive therapeutic effect and mechanism of the KDZI on CVDs. Ixeris sonchifolia extract injection, a Chinese medicine preparation named as Kudiezi injection (KDZI) in China, has been widely used for the treatment of cardiovascular diseases (CVDs) in recent years.![]()
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Ginsenosides: potential therapeutic source for fibrosis-associated human diseases. J Ginseng Res 2019; 44:386-398. [PMID: 32372860 PMCID: PMC7195584 DOI: 10.1016/j.jgr.2019.12.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/25/2019] [Accepted: 12/10/2019] [Indexed: 12/11/2022] Open
Abstract
Tissue fibrosis is an eventual pathologic change of numerous chronic illnesses, which is characterized by resident fibroblasts differentiation into myofibroblasts during inflammation, coupled with excessive extracellular matrix deposition in tissues, ultimately leading to failure of normal organ function. Now, there are many mechanistic insights into the pathogenesis of tissue fibrosis, which facilitate the discovery of effective antifibrotic drugs. Moreover, many chronic diseases remain a significant clinical unmet need. For the past five years, many research works have undoubtedly addressed the functional dependency of ginsenosides in different types of fibrosis and the successful remission in various animal models treated with ginsenosides. Caveolin-1, interleukin, thrombospondin-1 (TSP-1), liver X receptors (LXRs), Nrf2, microRNA-27b, PPARδ-STAT3, liver kinase B1 (LKB1)-AMPK, and TGF-β1/Smads are potential therapy targeting using ginsenosides. Ginsenosides can play a targeting role and suppress chronic inflammatory response, collagen deposition, and epithelial-mesenchymal transition (EMT), as well as myofibroblast activation to attenuate fibrosis. In this report, our aim was to focus on the therapeutic prospects of ginsenosides in fibrosis-related human diseases making use of results acquired from various animal models. These findings should provide important therapeutic clues and strategies for the exploration of new drugs for fibrosis treatment.
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Tate M, Prakoso D, Willis AM, Peng C, Deo M, Qin CX, Walsh JL, Nash DM, Cohen CD, Rofe AK, Sharma A, Kiriazis H, Donner DG, De Haan JB, Watson AMD, De Blasio MJ, Ritchie RH. Characterising an Alternative Murine Model of Diabetic Cardiomyopathy. Front Physiol 2019; 10:1395. [PMID: 31798462 PMCID: PMC6868003 DOI: 10.3389/fphys.2019.01395] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/28/2019] [Indexed: 12/21/2022] Open
Abstract
The increasing burden of heart failure globally can be partly attributed to the increased prevalence of diabetes, and the subsequent development of a distinct form of heart failure known as diabetic cardiomyopathy. Despite this, effective treatment options have remained elusive, due partly to the lack of an experimental model that adequately mimics human disease. In the current study, we combined three consecutive daily injections of low-dose streptozotocin with high-fat diet, in order to recapitulate the long-term complications of diabetes, with a specific focus on the diabetic heart. At 26 weeks of diabetes, several metabolic changes were observed including elevated blood glucose, glycated haemoglobin, plasma insulin and plasma C-peptide. Further analysis of organs commonly affected by diabetes revealed diabetic nephropathy, underlined by renal functional and structural abnormalities, as well as progressive liver damage. In addition, this protocol led to robust left ventricular diastolic dysfunction at 26 weeks with preserved systolic function, a key characteristic of patients with type 2 diabetes-induced cardiomyopathy. These observations corresponded with cardiac structural changes, namely an increase in myocardial fibrosis, as well as activation of several cardiac signalling pathways previously implicated in disease progression. It is hoped that development of an appropriate model will help to understand some the pathophysiological mechanisms underlying the accelerated progression of diabetic complications, leading ultimately to more efficacious treatment options.
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Affiliation(s)
- Mitchel Tate
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Darnel Prakoso
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,School of Biosciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Andrew M Willis
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Cheng Peng
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Minh Deo
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Cheng Xue Qin
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Jesse L Walsh
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - David M Nash
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Charles D Cohen
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Alex K Rofe
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Arpeeta Sharma
- Oxidative Stress Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Helen Kiriazis
- Preclinical Cardiology, Microsurgery and Imaging Platform, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Daniel G Donner
- Preclinical Cardiology, Microsurgery and Imaging Platform, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Judy B De Haan
- Oxidative Stress Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Anna M D Watson
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Miles J De Blasio
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,School of Biosciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Rebecca H Ritchie
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia
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41
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D'Amario D, Migliaro S, Borovac JA, Restivo A, Vergallo R, Galli M, Leone AM, Montone RA, Niccoli G, Aspromonte N, Crea F. Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction. Front Physiol 2019; 10:1347. [PMID: 31749710 PMCID: PMC6848263 DOI: 10.3389/fphys.2019.01347] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 10/10/2019] [Indexed: 12/19/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is an increasingly studied entity accounting for 50% of all diagnosed heart failure and that has claimed its own dignity being markedly different from heart failure with reduced EF in terms of etiology and natural history (Graziani et al., 2018). Recently, a growing body of evidence points the finger toward microvascular dysfunction as the major determinant of the pathological cascade that justifies clinical manifestations (Crea et al., 2017). The high burden of comorbidities such as metabolic syndrome, hypertension, atrial fibrillation, chronic kidney disease, obstructive sleep apnea, and similar, could lead to a systemic inflammatory state that impacts the physiology of the endothelium and the perivascular environment, engaging complex molecular pathways that ultimately converge to myocardial fibrosis, stiffening, and dysfunction (Paulus and Tschope, 2013). These changes could even self-perpetrate with a positive feedback where hypoxia and locally released inflammatory cytokines trigger interstitial fibrosis and hypertrophy (Ohanyan et al., 2018). Identifying microvascular dysfunction both as the cause and the maintenance mechanism of this condition has opened the field to explore specific pharmacological targets like nitric oxide (NO) pathway, sarcomeric titin, transforming growth factor beta (TGF-β) pathway, immunomodulators or adenosine receptors, trying to tackle the endothelial impairment that lies in the background of this syndrome (Graziani et al., 2018;Lam et al., 2018). Yet, many questions remain, and the new data collected still lack a translation to improved treatment strategies. To further elaborate on this tangled and exponentially growing topic, we will review the evidence favoring a microvasculature-driven etiology of this condition, its clinical correlations, the proposed diagnostic workup, and the available/hypothesized therapeutic options to address microvascular dysfunction in the failing heart.
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Affiliation(s)
- Domenico D'Amario
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Stefano Migliaro
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Josip A Borovac
- Department of Pathophysiology, University of Split School of Medicine, Split, Croatia
| | - Attilio Restivo
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Rocco Vergallo
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Mattia Galli
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Maria Leone
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Rocco A Montone
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giampaolo Niccoli
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Nadia Aspromonte
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Filippo Crea
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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Zhang Z, Wang J, Zhu Y, Zhang H, Wang H. Astragaloside IV alleviates myocardial damage induced by type 2 diabetes via improving energy metabolism. Mol Med Rep 2019; 20:4612-4622. [PMID: 31702040 PMCID: PMC6797977 DOI: 10.3892/mmr.2019.10716] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study was to evaluate the protective effect and mechanism of Astragaloside IV (ASIV) on myocardial injury induced by type 2 diabetes, with a focus on energy metabolism. Blood glucose, the hemodynamic index, left ventricular weight/heart weight (LVW/HW), the left ventricular systolic pressure (LVSP), the left ventricular end diastolic pressure (LVEDP) and cell survival rate were measured in streptozotocin‑induced diabetes model rats. Western blot analysis, PCR, hematoxylin‑eosin and TUNEL staining, flow cytometry and ELISA were used to detect: i) Cardiomyocyte damage indicators such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cytochrome c (Cyt C), caspase‑3, cleaved caspase‑3 and the apoptotic rate; ii) energy metabolism indicators such as ATP/AMP and ADP/AMP; and iii) energy metabolism associated pathway proteins such as peroxisome proliferator‑activated receptor γ coactivator 1‑α (PGC‑1α) and nuclear respiratory factor 1 (NRF1). The present demonstrated increased blood glucose, LVW/HW, LVSP, LVEDP and the cardiomyocyte damage indicators (ANP, BNP, Cyt C and caspase‑3), in the diabetic and high glucose‑treated groups, which were decreased by ASIV. The expression of NRF‑1 and PGC‑1α significantly changed in the model group and was markedly improved following ASIV treatment. Furthermore, the abnormal energy metabolism in the model group was reversed by ASIV. According to the results, ASIV can regulate energy metabolism by regulating the release of PGC‑1α and NRF1 to rescue the abnormal energy metabolism caused by diabetes mellitus, thus decreasing the myocardial damage caused by diabetic cardiomyopathy.
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Affiliation(s)
- Zhen Zhang
- Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Jing Wang
- The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Yingwei Zhu
- Institute of Physical Education, Bohai University, Jinzhou, Liaoning 121013, P.R. China
| | - Hui Zhang
- Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Hongxin Wang
- Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
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Ibrahim KA, Khwanes SA, El-Desouky MA, Elhakim HKA. Propolis relieves the cardiotoxicity of chlorpyrifos in diabetic rats via alleviations of paraoxonase-1 and xanthine oxidase genes expression. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2019; 159:127-135. [PMID: 31400774 DOI: 10.1016/j.pestbp.2019.06.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/20/2019] [Accepted: 06/07/2019] [Indexed: 02/07/2023]
Abstract
Pesticides cardiotoxicity in case of diabetic-induced cardiac complications is unidentified. The probable amelioration role of propolis is gauged against the cardiotoxic effects of chlorpyrifos in the diabetic rats through paraoxonase-1 (PON1) and xanthine oxidase (XO) genes dysregulation. Fifty-six male rats were distributed (n = 7) into eight groups. The first one saved as control whereas the 2nd, 3rd, and 4th were kept for propolis aqueous extract (100 mg/kg), diabetes (60 mg/kg streptozotocin) and chlorpyrifos (2.5 mg/kg), respectively. The 5th was diabetes/chlorpyrifos combination, while 6th, 7th, and 8th were intubated with propolis for four weeks after diabetic induction, chlorpyrifos intoxication, and their combination, respectively. The plasma glucose, lipid profiles, cardiac enzymes and interleukin-6 (IL-6) significantly elevated, while insulin decreased in the diabetic and combination groups. Although the cardiac acetylcholinesterase, total thiols, and PON1 significantly reduced after diabetic and/or chlorpyrifos gavage, the protein carbonyl, superoxide dismutase, catalase, and XO significantly elevated. The mRNA genes expression of PON1 and XO have also confirmed the enzymatic activities. Interestingly, propolis significantly restored the hyperglycemia, hypoinsulinemia, hyperlipidemia, IL-6 elevations, and antioxidant defense system disorder. These records revealed that the immunomodulatory, anti-diabetic and antioxidant tasks are fine pointers for the cardiovascular defender of propolis especially during diabetes and/or pesticides exposure.
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Affiliation(s)
- Khairy A Ibrahim
- Mammalian Toxicology Department, Central Agricultural Pesticides Laboratory, Agricultural Research Center, Dokki, Giza, 12618, Egypt.
| | - Soad A Khwanes
- Mammalian Toxicology Department, Central Agricultural Pesticides Laboratory, Agricultural Research Center, Dokki, Giza, 12618, Egypt
| | | | - Heba K A Elhakim
- Biochemistry Division, Faculty of Science, Cairo University, Giza 12613, Egypt
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Pires KM, Torres NS, Buffolo M, Gunville R, Schaaf C, Davis K, Selzman CH, Gottlieb RA, Boudina S. Suppression of Cardiac Autophagy by Hyperinsulinemia in Insulin Receptor-Deficient Hearts Is Mediated by Insulin-Like Growth Factor Receptor Signaling. Antioxid Redox Signal 2019; 31:444-457. [PMID: 31088290 PMCID: PMC6653796 DOI: 10.1089/ars.2018.7640] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Aims: Autophagy is a catabolic process required for the maintenance of cardiac health. Insulin and insulin-like growth factor 1 (IGF-1) are potent inhibitors of autophagy and as such, one would predict that autophagy will be increased in the insulin-resistant/diabetic heart. However, autophagy is rather decreased in the hearts of diabetic/insulin-resistant mice. The aim of this study is to determine the contribution of IGF-1 receptor signaling to autophagy suppression in insulin receptor (IR)-deficient hearts. Results: Absence of IRs in the heart was associated with reduced autophagic flux, and further inhibition of autophagosome clearance reduced survival, impaired contractile function, and enhanced myocyte loss. Contrary to the in vivo setting, isolated cardiomyocytes from IR-deficient hearts exhibited unrestrained autophagy in the absence of insulin, whereas addition of insulin was able to suppress autophagy. To investigate the mechanisms involved in the maintenance of the responsiveness to insulin in IR-deficient hearts, we generated mice lacking both IRs and one copy of the IGF-1 receptor (IGF-1R) in cardiac cells and showed that these mice had increased autophagy. Innovation and Conclusion: This study unveils a new mechanism by which IR-deficient hearts can still respond to insulin to suppress autophagy, in part, through activation of IGF-1R signaling. This is a highly significant observation because it is the first to show that systemic hyperinsulinemia can suppress autophagy in IR-deficient hearts through IGF-1R signaling.
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Affiliation(s)
- Karla Maria Pires
- 1 Department of Nutrition and Integrative Physiology, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Natalia S Torres
- 2 Nora Eccles Harrison Cardiovascular Research and Training Institute, Salt Lake City, Utah
| | - Marcio Buffolo
- 1 Department of Nutrition and Integrative Physiology, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - River Gunville
- 1 Department of Nutrition and Integrative Physiology, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Christin Schaaf
- 3 Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, Utah
| | - Kathryn Davis
- 2 Nora Eccles Harrison Cardiovascular Research and Training Institute, Salt Lake City, Utah
| | - Craig H Selzman
- 3 Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, Utah
| | - Roberta A Gottlieb
- 4 The Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, California
| | - Sihem Boudina
- 1 Department of Nutrition and Integrative Physiology, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
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45
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Bowman PRT, Smith GL, Gould GW. GLUT4 expression and glucose transport in human induced pluripotent stem cell-derived cardiomyocytes. PLoS One 2019; 14:e0217885. [PMID: 31344028 PMCID: PMC6657831 DOI: 10.1371/journal.pone.0217885] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 07/15/2019] [Indexed: 01/07/2023] Open
Abstract
Induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) have the potential to transform regenerative cardiac medicine and the modelling of cardiac disease. This is of particular importance in the context of diabetic cardiomyopathy where diabetic individuals exhibit reduced cardiac diastolic contractile performance in the absence of vascular disease, significantly contributing towards high cardiovascular morbidity. In this study, the capacity of iPSC-CM to act as a novel cellular model of cardiomyocytes was assessed. The diabetic phenotype is characterised by insulin resistance, therefore there was a specific focus upon metabolic parameters. Despite expressing crucial insulin signalling intermediates and relevant trafficking proteins, it was identified that iPSC-CM do not exhibit insulin-stimulated glucose uptake. iPSC-CM are spontaneously contractile however contraction mediated uptake was not found to mask any insulin response. The fundamental limitation identified in these cells was a critical lack of expression of the insulin sensitive glucose transporter GLUT4. Using comparative immunoblot analysis and the GLUT-selective inhibitor BAY-876 to quantify expression of these transporters, we show that iPSC-CM express high levels of GLUT1 and low levels of GLUT4 compared to primary cardiomyocytes and cultured adipocytes. Interventions to overcome this limitation were unsuccessful. We suggest that the utility of iPSC-CMs to study cardiac metabolic disorders may be limited by their apparent foetal-like phenotype.
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Affiliation(s)
- Peter R T Bowman
- Henry Wellcome Laboratory of Cell Biology, Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Godfrey L Smith
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Gwyn W Gould
- Henry Wellcome Laboratory of Cell Biology, Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Abstract
Non-communicable diseases, such as cardiovascular diseases, are the leading cause of mortality worldwide. For this reason, a tremendous effort is being made worldwide to effectively circumvent these afflictions, where insulin-like growth factor 1 (IGF1) is being proposed both as a marker and as a central cornerstone in these diseases, making it an interesting molecule to focus on. Firstly, at the initiation of metabolic deregulation by overfeeding, IGF1 is decreased/inhibited. Secondly, such deficiency seems to be intimately related to the onset of MetS and establishment of vascular derangements leading to atherosclerosis and finally playing a definitive part in cerebrovascular and myocardial accidents, where IGF1 deficiency seems to render these organs vulnerable to oxidative and apoptotic/necrotic damage. Several human cohort correlations together with basic/translational experimental data seem to confirm deep IGF1 implication, albeit with controversy, which might, in part, be given by experimental design leading to blurred result interpretation.
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Zhao T, Chen H, Xu F, Wang J, Liu Y, Xing X, Guo L, Zhang M, Lu Q. Liraglutide alleviates cardiac fibrosis through inhibiting P4hα-1 expression in STZ-induced diabetic cardiomyopathy. Acta Biochim Biophys Sin (Shanghai) 2019; 51:293-300. [PMID: 30883649 DOI: 10.1093/abbs/gmy177] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 12/25/2018] [Indexed: 01/09/2023] Open
Abstract
Diabetic cardiomyopathy is an important contributor to morbidity and mortality of diabetic patients by causing heart failure. Interstitial and perivascular fibrosis plays a crucial role in diabetic cardiomyopathy. However, there is a lack of effective specific treatments available for diabetic cardiomyopathy. In the present study, we aim to explore the effects of Liraglutide, a GLP-1 analogue, on diabetic cardiomyopathy in STZ-induced diabetic rats fed with high-fat diet. A total of 60 male Wistar rats were randomly assigned to three groups, i.e. normal group, model group, and Liraglutide group, with 20 rats in each group. Serum levels of TC, TG, LDL-C, NEFA, and hydroxyproline were measured using commercial kits. Cardiac function was evaluated by QRS waves, LVEDd, LVESd, and LVEF. Myocardial fibrosis was measured by immunohistochemistry. Our results demonstrated that chronic administration of Liraglutide decreased the level of blood glucose and significantly alleviated lipid metabolic disturbance compared with the model group. Furthermore, Liraglutide was found to improve the damaged cardiac function. In line with this, we also found that the alleviation of cardiac dysfunction was associated with the decreased fibrosis in diabetic myocardial tissues, which was reflected by the decreased expressions of P4hα-1, COL-1, COL-3, MMP-1, and MMP-9. Our results thus suggest that Liraglutide might have a myocardial protective effect by inhibiting P4hα-1-mediated myocardial fibrosis.
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Affiliation(s)
- Tong Zhao
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
| | - Huiqiang Chen
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
| | - Fei Xu
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
| | - Juan Wang
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
| | - Yusheng Liu
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
| | - Xiaowei Xing
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
| | - Linlin Guo
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
| | - Mingxiang Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research of the Chinese Ministry of Education and Public Health, Shandong University Qilu Hospital, Jinan, China
| | - Qinghua Lu
- Department of Cardiology, the Second Hospital of Shandong University, Jinan, China
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Cai H, Chen S, Liu J, He Y. An attempt to reverse cardiac lipotoxicity by aerobic interval training in a high-fat diet- and streptozotocin-induced type 2 diabetes rat model. Diabetol Metab Syndr 2019; 11:43. [PMID: 31249632 PMCID: PMC6567651 DOI: 10.1186/s13098-019-0436-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 05/17/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is an important risk factor for cardiovascular disease. Aerobic interval training (AIT) has been recommended to patients as a non-pharmacological strategy to manage DM. However, little is known about whether AIT intervention at the onset of DM will reverse the process of diabetic cardiomyopathy (DCM). In this study, we sought to evaluate whether AIT can reverse the process of DCM and explore the underlying mechanisms. METHODS Fifty Wistar rats were randomly divided into a control group (CON), DCM group (DCM) and AIT intervention group (AIT). A high-fat diet and streptozotocin (STZ) were used to induce diabetes in rats in the DCM group and AIT group. Rats in the AIT group were subjected to an 8-week AIT intervention. Fasting blood glucose (FBG), lipid profiles and insulin levels were measured. Haematoxylin and eosin (HE) staining and oil red O staining were used to identify cardiac morphology and lipid accumulation, respectively. Serum BNP levels and cardiac BNP mRNA expression were measured to ensure the safety of the AIT intervention. Free fatty acid (FFA) and diacylglycerol (DAG) concentrations were analysed by enzymatic methods. AMPK, p-AMPK, FOXO1, CD36 and PPARα gene and protein expression were detected by RT-PCR and Western blotting. RESULTS AIT intervention significantly reduced rat serum cardiovascular disease risk factors in DCM rats (P < 0.05). The safety of AIT intervention was illustrated by reduced serum BNP levels and cardiac BNP mRNA expression (P < 0.05) after AIT intervention in DCM rats histological analysis and FFA and DAG concentrations revealed that AIT intervention reduced the accumulation of lipid droplets within cardiomyocytes and alleviated cardiac lipotoxicity (P < 0.05). CD36 and PPARα gene and protein expression were elevated in the DCM group, and these increases were reduced by AIT intervention (P < 0.01). The normalized myocardial lipotoxicity was due to increased expression of phosphorylated AMPK and reduced FOXO1 expression after AIT intervention. CONCLUSION AIT intervention may alleviate cardiac lipotoxicity and reverse the process of DCM through activation of the AMPK-FOXO1 pathway.
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Affiliation(s)
- Huan Cai
- Institute of Physical Education, Hebei Normal University, Shijiazhuang, China
| | - Shuchun Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Jingqin Liu
- Department of Endocrinology, NO. 1 Hospital of Baoding, Baoding, China
| | - Yuxiu He
- Institute of Physical Education, Hebei Normal University, Shijiazhuang, China
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MicroRNA-503 regulates hypoxia-induced cardiomyocytes apoptosis through PI3K/Akt pathway by targeting IGF-1R. Biochem Biophys Res Commun 2018; 506:1026-1031. [PMID: 30404731 DOI: 10.1016/j.bbrc.2018.10.160] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 10/19/2018] [Accepted: 10/26/2018] [Indexed: 12/26/2022]
Abstract
Coronary heart disease is the second highest specific cause of death. H9c2 cardiomyocytes were subjected to hypoxia (1% O2) for 0, 6, 12, 24 and 48 h. Cell apoptosis and the activity of caspase3/7 was detected using ELISA; western blot was applied to determine the cleaved-caspase3 (c-caspase3), cleaved-PARP (c-PARP) and cytochrome C (Cyto C) expression after the inhibitor negative control (in-NC), miR-503 inhibitor, mimic negative control (mi-NC) and miR-503 mimic were transfected into cells for 48 h. Moreover, flow cytometry was applied to evaluate mitochondrial membrane potential. In addition, luciferase reporter gene assay was used for detection the relationship between miR-503 and insulin-like growth-factor-1 receptor (IGF-1R). Real-time PCR showed microRNA-503 (miR-503) was elevated in a time-dependent manner under hypoxia. MiR-503 inhibition prevented cell apoptosis and reduced caspase3/7 activity and the expression of c-caspase3 and c-PARP, prevented mitochondrial membrane potential collapse and reduced the cyto C level in cytosol. While, miR-503 overexpression showed a pro-apoptotic role and resulted in mitochondrial membrane potential loss. MiR-503 directly targets IGF-1R in H9c2 cardiomyocytes. The depletion of IGF-1R using a specific IGF-1R siRNA (siIGF-1R) abolished anti-apoptotic function of miR-503 inhibitor, and LY294002 showed a similar trend. In summary, miR-503 promoted cell apoptosis, caused mitochondrial membrane potential collapse and the emancipation of cyto C from mitochondrial through PI3K/Akt pathway via targeting IGF-1R in H9c2 cardiomyocytes.
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Borghetti G, von Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M. Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. Front Physiol 2018; 9:1514. [PMID: 30425649 PMCID: PMC6218509 DOI: 10.3389/fphys.2018.01514] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/09/2018] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus and the associated complications represent a global burden on human health and economics. Cardiovascular diseases are the leading cause of death in diabetic patients, who have a 2–5 times higher risk of developing heart failure than age-matched non-diabetic patients, independent of other comorbidities. Diabetic cardiomyopathy is defined as the presence of abnormal cardiac structure and performance in the absence of other cardiac risk factors, such coronary artery disease, hypertension, and significant valvular disease. Hyperglycemia, hyperinsulinemia, and insulin resistance mediate the pathological remodeling of the heart, characterized by left ventricle concentric hypertrophy and perivascular and interstitial fibrosis leading to diastolic dysfunction. A change in the metabolic status, impaired calcium homeostasis and energy production, increased inflammation and oxidative stress, as well as an accumulation of advanced glycation end products are among the mechanisms implicated in the pathogenesis of diabetic cardiomyopathy. Despite a growing interest in the pathophysiology of diabetic cardiomyopathy, there are no specific guidelines for diagnosing patients or structuring a treatment strategy in clinical practice. Anti-hyperglycemic drugs are crucial in the management of diabetes by effectively reducing microvascular complications, preventing renal failure, retinopathy, and nerve damage. Interestingly, several drugs currently in use can improve cardiac health beyond their ability to control glycemia. GLP-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors have been shown to have a beneficial effect on the cardiovascular system through a direct effect on myocardium, beyond their ability to lower blood glucose levels. In recent years, great improvements have been made toward the possibility of modulating the expression of specific cardiac genes or non-coding RNAs in vivo for therapeutic purpose, opening up the possibility to regulate the expression of key players in the development/progression of diabetic cardiomyopathy. This review summarizes the pathogenesis of diabetic cardiomyopathy, with particular focus on structural and molecular abnormalities occurring during its progression, as well as both current and potential future therapies.
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Affiliation(s)
- Giulia Borghetti
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Dirk von Lewinski
- Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Deborah M Eaton
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Steven R Houser
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Markus Wallner
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.,Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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