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Cox D, Byrne B, Hammers DW, Landry J, Sweeney HL. Effect of Tadalafil on cardiac function and left ventricular dimensions in Duchenne muscular dystrophy: safety and cardiac MRI substudy results from a randomized, placebo-controlled trial. BMC Cardiovasc Disord 2025; 25:276. [PMID: 40217158 PMCID: PMC11987275 DOI: 10.1186/s12872-025-04727-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND Inhibition of phosphodiesterase 5 (PDE5) was hypothesized to slow disease progression in Duchenne muscular dystrophy (DMD). Tadalafil, a once-daily PDE5 inhibitor, did not slow loss of ambulation in a phase 3 placebo-controlled trial. This report details the cardiac findings from this study. METHODS Patients with DMD (N = 331) aged 7 to 14 years on stable glucocorticoids were randomized to tadalafil 0.3 mg/kg/day, 0.6 mg/kg/day, or placebo. Ejection fraction (EF), fractional shortening, and M-mode ventricular dimensions were measured on echocardiograms. 12-lead ECGs were centrally evaluated for heart rate and intervals, and qualitative diagnoses. Vital signs and unsolicited adverse events were collected throughout the study. Cardiac MRI (CMR) was collected in a subset of 27 patients. Z-scores for ventricular dimensions and volumes were calculated based on published age-normative reference values. Treatment differences for change in continuous ECG parameters and vital signs were compared using Wilcoxon rank-sum tests. Echocardiogram and CMR parameters were analyzed with an ANCOVA model. RESULTS Tadalafil had no adverse effects on echocardiographic left ventricular (LV) EF or fractional shortening, ECG findings, or vital signs. Mean diastolic LV internal dimension (LVIDd) was increased in the tadalafil 0.6 mg/kg group versus placebo at Week 24 (+ 0.13 cm, p =.019) and Week 48 (+ 0.18 cm, p =.008), with a similar pattern observed for LV systolic dimensions (LVIDs). Mean LV end diastolic volume (EDV) measured by CMR also increased at Week 48 in the tadalafil 0.3 mg/kg (+ 13.0 ml, p =.047 vs. placebo) and 0.6 mg/kg (+ 12.0 ml, p =.08 vs. placebo) groups, with numerically smaller increases in LV EDV and commensurate increases in stroke volume and cardiac output. Z-scores for LVIDd and LV EDV were generally below the normal range at baseline and increased toward or within the normal range in the tadalafil groups but not in the placebo group. CONCLUSIONS No adverse effects of tadalafil on cardiovascular function were evident based on adverse events, echocardiograms, ECG, or vital sign measurements through 48 weeks in patients with DMD. The small mean increases in LVID and LV volume observed with tadalafil are consistent with PDE5 inhibitor pharmacology, but their clinical relevance in the context of LV tonic contraction in DMD is unknown and deserve further study. CLINICALTRIALS GOV IDENTIFIER NCT01865084 (first registration date: 24-May-2013).
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Affiliation(s)
- David Cox
- Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, 893 S. Delaware Street, Indianapolis, IN, 46285, USA.
| | | | | | - John Landry
- Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, 893 S. Delaware Street, Indianapolis, IN, 46285, USA
- Eli Lilly Canada, Eli Lilly and Company, Toronto, ON, Canada
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Pei Z, Fan J, Tang M, Li Y. Ferroptosis: A New Strategy for the Treatment of Fibrotic Diseases. Adv Biol (Weinh) 2025; 9:e2400383. [PMID: 39377183 DOI: 10.1002/adbi.202400383] [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: 07/02/2024] [Revised: 09/07/2024] [Indexed: 10/09/2024]
Abstract
Ferroptosis is a new type of cell death characterized by iron dependence and the excessive accumulation of lipid reactive oxygen species (lipid ROS) that has gradually become better characterized. There is sufficient evidence indicating that ferroptosis is associated with a variety of human life activities and diseases, such as tumor suppression, ischemic organ injury, and degenerative disorders. Notably, ferroptosis is also involved in the initiation and development of fibrosis in various organs, including liver fibrosis, pulmonary fibrosis, renal fibrosis, and cardiac fibrosis, which is usually irreversible and refractory. Although a large number of patients with fibrosis urgently need to be treated, the current treatment options are still limited and unsatisfactory. Organ fibrosis involves a series of complex and orderly processes, such as parenchymal cell damage, recruitment of inflammatory cells and activation of fibroblasts, which ultimately leads to the accumulation of extracellular matrix (ECM) and the formation of fibrosis. An increasing number of studies have confirmed the close association between these pathological processes and ferroptosis. This review summarizes the role and function of ferroptosis in fibrosis and proposes several potential therapeutic strategies and pathways based on ferroptosis.
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Affiliation(s)
- Zhuo Pei
- Air Force Hospital of the Central Theater Command of PLA, Datong, 037006, China
| | - Jing Fan
- Air Force Hospital of the Northern Theater Command of the People's Liberation Army of China, Shenyang, 110044, China
| | - Maolin Tang
- Air Force Hospital of the Central Theater Command of PLA, Datong, 037006, China
| | - Yuhong Li
- Department of Cell Biology, Army Medical University, Chongqing, 400038, China
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Kim J, Zhao R, Kleinberg LR, Kim K. Effect of long and short half-life PDE5 inhibitors on HbA1c levels: a systematic review and meta-analysis. EClinicalMedicine 2025; 80:103035. [PMID: 39844934 PMCID: PMC11751502 DOI: 10.1016/j.eclinm.2024.103035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
Background Phosphodiesterase 5 (PDE5) inhibitors, owing to their mechanism of action, have been gaining recognition as a potential case of drug repurposing and combination therapy for diabetes treatment. We aimed to examine the effect of long and short half-life PDE5 inhibitors have on Haemoglobin A1c (HbA1c) levels. Methods A systematic review and meta-analysis was conducted of randomised controlled trials (RCTs) in people with elevated HbA1c (>6%) to assess mean difference in HbA1c levels from baseline versus controls after any PDE5 inhibitor intervention of ≥4 weeks, excluding multiple interventions. Cochrane CENTRAL, PMC Medline, ClinicalTrials.gov, and WHO ICTRP were searched without language restrictions up to September 30, 2024. Summary data from published data were extracted. PRISMA and Cochrane guidelines used to extract and assess data using a random-effects meta-analysis. This study is registered with the Research Registry, reviewregistry1733. Findings Among 1096 studies identified, in analysis of 13 studies with 1083 baseline patients, long half-life PDE5 inhibitors (tadalafil, PF-00489791) had decreases in HbA1c while short half-life PDE5 inhibitors (sildenafil, avanafil) had no change. Five (38.5%) studies had a low risk of bias, and eight (61.5%) had some concerns. Long half-life inhibitors had significant mean decrease of -0.40% ([-0.66, -0.14], p = 0.002, I2 = 82%, 7.70% baseline HbA1c). Short half-life inhibitors had insignificant mean difference of +0.08% ([-0.16, 0.33], p = 0.51, I2 = 40%, 7.73% baseline HbA1c). In ≥8-week trials with participants with type 2 diabetes (T2D) and mean HbA1c ≥ 6.5%, long half-life inhibitors had significant mean decrease of -0.50% ([-0.83, -0.17], I2 = 88%, p = 0.003); short half-life inhibitors had significant mean increase of +0.36% ([0.03, 0.68], I2 = 3%, p = 0.03). Interpretation At the well-controlled HbA1c of the participants, previous literature shows current diabetes treatments have similar HbA1c decreases, so the HbA1c mean difference of long half-life PDE5 inhibitors may indeed be clinically relevant. This suggests future investigation into PDE5 inhibitors as part of combination therapy or as therapy for high HbA1c individuals is needed, especially because of variable risk of biases, homogeneity, and sample sizes in our study. Funding None.
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Affiliation(s)
- Joseph Kim
- Department of Biophysics, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD, 21218, USA
| | - Rui Zhao
- Department of Biochemistry and Molecular Genetics, University of Alabama Birmingham Heersink School of Medicine, Room 714, 1825 University Blvd., Birmingham, AL, 35294-2182, USA
| | - Lawrence Richard Kleinberg
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 401 N. Broadway, Baltimore, MD, 21231, USA
| | - Kitai Kim
- Human Stem Cell and Genome Engineering Center, University of California Los Angeles David Geffen School of Medicine, UCLA - CHS 36 - 125/133/143 650 Charles E. Young Dr. South, Los Angeles, CA, 90095, USA
- Department of Biological Chemistry, University of California Los Angeles David Geffen School of Medicine, UCLA - CHS 36 - 125/133/143 650 Charles E. Young Dr. South, Los Angeles, CA, 90095, USA
- Virginia University of Integrative Medicine, 1980 Gallows Road, Vienna, VA, 22182, USA
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Sansone A, Guida E, Dolci S, Frangione V, Asso A, Bellia G, Jannini EA. Future perspectives for PDE5 inhibitors bridging the gap between cardiovascular health and psychological status. Basic Clin Androl 2025; 35:3. [PMID: 39865236 PMCID: PMC11771123 DOI: 10.1186/s12610-024-00245-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 11/30/2024] [Indexed: 01/28/2025] Open
Abstract
The serendipitous discovery that inhibiting type 5 phosphodiesterase (PDE5) using sildenafil, a potent PDE5 inhibitor (PDE5i) initially developed for cardioprotection, introduced the possibility of orally managing erectile dysfunction (ED) led to an increase in research data, which are currently considered groundbreaking for the new discipline of sexual medicine. Findings from a number of laboratories and clinics around the world unanimously demonstrated the following: (i) the major cause of ED is directly or indirectly related to cardiovascular disease (CVD); (ii) ED and CVDs share the same risk factors, which are related mainly to lifestyle choices; (iii) the first therapeutic approach to both ED and CVDs is to transform harmful lifestyles into virtuous lifestyles; and (iv) PDE5is in general, particularly sildenafil, are very safe, if not protective, for use in CVD patients. However, the use of PDE5is has faced several challenges. Many patients and some healthcare providers (HCPs) often share the misconception that using these drugs can increase the risk of CVD. Some patients might desire to fulfill the unmet need for privacy linked to the stigma of being treated for ED or might be enticed by the idea of buying drugs online, either because of shame or cheaper prices, without knowing the risks associated with counterfeit drugs. The aim of this narrative revision of the current literature is to demonstrate that (i) the orodispersible film of sildenafil is safe from a CV perspective; (ii) it is a discreet formulation that respects the need for privacy; and (iii) it is virtually the unique PDE5i formulation too expensive to produce outside the correct channels, making it impossible to be counterfeit.
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Affiliation(s)
- Andrea Sansone
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Dept. of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, Rome, 00133, Italy
| | - Eugenia Guida
- Chair of Anatomy, Dept. of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Susanna Dolci
- Chair of Anatomy, Dept. of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | | | | | | | - Emmanuele A Jannini
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Dept. of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, Rome, 00133, Italy.
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Paronetto MP, Crescioli C. Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health. Front Endocrinol (Lausanne) 2024; 15:1461642. [PMID: 39355618 PMCID: PMC11442314 DOI: 10.3389/fendo.2024.1461642] [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: 07/08/2024] [Accepted: 08/28/2024] [Indexed: 10/03/2024] Open
Abstract
The phosphodiesterases type 5 (PDE5) are catalytic enzymes converting the second messenger cyclic guanosine monophosphate (cGMP) to 5' GMP. While intracellular cGMP reduction is associated with several detrimental effects, cGMP stabilization associates with numerous benefits. The PDE5 specific inhibitors, PDE5i, found their explosive fortune as first-line treatment for erectile dysfunction (ED), due to their powerful vasoactive properties. The favorable effect for ED emerged as side-effect when PDE5i were originally proposed for coronary artery disease (CAD). From that point on, the use of PDE5i captured the attention of researchers, clinicians, and companies. Indeed, PDE5-induced intracellular cGMP stabilization offers a range of therapeutic opportunities associated not only with vasoactive effects, but also with immune regulatory/anti-inflammatory actions. Chronic inflammation is acknowledged as the common link underlying most non-communicable diseases, including metabolic and cardiac diseases, autoimmune and neurodegenerative disorders, cancer. In this scenario, the clinical exploitation of PDE5i is undeniably beyond ED, representing a potential therapeutic tool in several human diseases. This review aims to overview the biological actions exerted by PDE5i, focusing on their ability as modulators of inflammation-related human diseases, with particular attention to inflammatory-related disorders, like cardiac diseases and cancer.
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Affiliation(s)
- Maria Paola Paronetto
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy
- Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, IRCCS, Rome, Italy
| | - Clara Crescioli
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy
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Curtis L. Erectile dysfunction drugs are essential and probably life-saving and should be provided to all men who need them just as birth control should be provided to all women who need them. Int J Impot Res 2024; 36:537-538. [PMID: 37443301 DOI: 10.1038/s41443-023-00736-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/30/2023] [Accepted: 07/05/2023] [Indexed: 07/15/2023]
Affiliation(s)
- Luke Curtis
- East Carolina University, Hazelwood, MO, USA.
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7
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Fu Q, Wang Y, Yan C, Xiang YK. Phosphodiesterase in heart and vessels: from physiology to diseases. Physiol Rev 2024; 104:765-834. [PMID: 37971403 PMCID: PMC11281825 DOI: 10.1152/physrev.00015.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 10/17/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels. Dysregulation of PDEs has been linked to the development of several cardiovascular diseases, such as hypertension, aneurysm, atherosclerosis, arrhythmia, and heart failure. Targeting these enzymes has been proven effective in treating cardiovascular diseases and is an attractive and promising strategy for the development of new drugs. In this review, we discuss the current understanding of the complex regulation of PDE isoforms in cardiovascular function, highlighting the divergent and even opposing roles of PDE isoforms in different pathogenesis.
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Affiliation(s)
- Qin Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Ying Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Chen Yan
- Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York, United States
| | - Yang K Xiang
- Department of Pharmacology, University of California at Davis, Davis, California, United States
- Department of Veterans Affairs Northern California Healthcare System, Mather, California, United States
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8
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Radzioch E, Dąbek B, Balcerczyk-Lis M, Frąk W, Fularski P, Młynarska E, Rysz J, Franczyk B. Diabetic Cardiomyopathy-From Basics through Diagnosis to Treatment. Biomedicines 2024; 12:765. [PMID: 38672121 PMCID: PMC11048005 DOI: 10.3390/biomedicines12040765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is the development of myocardial dysfunction in patients with diabetes despite the absence of comorbidities such as hypertension, atherosclerosis or valvular defect. The cardiovascular complications of poorly controlled diabetes are very well illustrated by the U.K. Prospective Diabetes Study (UKPDS), which showed a clear association between increasing levels of glycated hemoglobin and the development of heart failure (HF). The incidence of HF in patients with diabetes is projected to increase significantly, which is why its proper diagnosis and treatment is so important. Providing appropriate therapy focusing on antidiabetic and hypolipemic treatment with the consideration of pharmacotherapy for heart failure reduces the risk of CMD and reduces the incidence of cardiovascular complications. Health-promoting changes made by patients such as a low-carbohydrate diet, regular exercise and weight reduction also appear to be important in achieving appropriate outcomes. New hope for the development of therapies for DCM is offered by novel methods using stem cells and miRNA, which, however, require more thorough research to confirm their efficacy.
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Affiliation(s)
- Ewa Radzioch
- Department of Nephrocardiology, Medical Univeristy of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Bartłomiej Dąbek
- Department of Nephrocardiology, Medical Univeristy of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Marta Balcerczyk-Lis
- Department of Nephrocardiology, Medical Univeristy of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Weronika Frąk
- Department of Nephrocardiology, Medical Univeristy of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Piotr Fularski
- Department of Nephrocardiology, Medical Univeristy of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical Univeristy of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical Univeristy of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
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9
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Pușcașu C, Zanfirescu A, Negreș S, Șeremet OC. Exploring the Multifaceted Potential of Sildenafil in Medicine. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2190. [PMID: 38138293 PMCID: PMC10744870 DOI: 10.3390/medicina59122190] [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: 11/30/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023]
Abstract
Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil's therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil's broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application.
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Affiliation(s)
| | - Anca Zanfirescu
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.); (O.C.Ș.)
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10
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Saha S, Fang X, Green CD, Das A. mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy. Int J Mol Sci 2023; 24:15078. [PMID: 37894760 PMCID: PMC10606418 DOI: 10.3390/ijms242015078] [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: 09/01/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023] Open
Abstract
Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.
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Affiliation(s)
- Sumit Saha
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Xianjun Fang
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Christopher D. Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Anindita Das
- Division of Cardiology, Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
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Zhang XJ, Han XW, Jiang YH, Wang YL, He XL, Liu DH, Huang J, Liu HH, Ye TC, Li SJ, Li ZR, Dong XM, Wu HY, Long WJ, Ni SH, Lu L, Yang ZQ. Impact of inflammation and anti-inflammatory modalities on diabetic cardiomyopathy healing: From fundamental research to therapy. Int Immunopharmacol 2023; 123:110747. [PMID: 37586299 DOI: 10.1016/j.intimp.2023.110747] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/18/2023] [Accepted: 07/29/2023] [Indexed: 08/18/2023]
Abstract
Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However, treatment options for DCM remain limited. For decades, a substantial body of evidence has suggested that the inflammatory response plays a pivotal role in the development and progression of DCM. Notably, DCM is closely associated with alterations in inflammatory cells, exerting direct effects on major resident cells such as cardiomyocytes, vascular endothelial cells, and fibroblasts. These cellular changes subsequently contribute to the development of DCM. This article comprehensively analyzes cellular, animal, and human studies to summarize the latest insights into the impact of inflammation on DCM. Furthermore, the potential therapeutic effects of current anti-inflammatory drugs in the management of DCM are also taken into consideration. The ultimate goal of this work is to consolidate the existing literature on the inflammatory processes underlying DCM, providing clinicians with the necessary knowledge and tools to adopt a more efficient and evidence-based approach to managing this condition.
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Affiliation(s)
- Xiao-Jiao Zhang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Xiao-Wei Han
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Yan-Hui Jiang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Ya-Le Wang
- Shanghai University of Traditional Chinese Medicine, 1200 Cai lun Road, Pudong New District, Shanghai 201203, China; Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, 16 Xian tong Road, Luo hu District, Shenzhen, Guangdong 518004, China
| | - Xing-Ling He
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Dong-Hua Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Jie Huang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Hao-Hui Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Tao-Chun Ye
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Si-Jing Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Zi-Ru Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Xiao-Ming Dong
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Hong-Yan Wu
- Shanghai University of Traditional Chinese Medicine, 1200 Cai lun Road, Pudong New District, Shanghai 201203, China; Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, 16 Xian tong Road, Luo hu District, Shenzhen, Guangdong 518004, China.
| | - Wen-Jie Long
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
| | - Shi-Hao Ni
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
| | - Lu Lu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
| | - Zhong-Qi Yang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
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Sorour OA, Nassar E, Sarhan N, El-Anwar N, ElKholy RA, Tahoon DM, Sweilam A, Tadros D. Chronic sildenafil citrate use decreases retinal vascular endothelial growth factor expression in diabetic rats: a pilot study. Int J Retina Vitreous 2023; 9:42. [PMID: 37460929 PMCID: PMC10351124 DOI: 10.1186/s40942-023-00480-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 07/01/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Sildenafil citrate (SC) attenuates endothelial dysfunction. However, its effects on diabetic retinopathy (DR), which is mainly a microvascular disease, remain unclear. Vascular endothelial growth factor (VEGF) is known to be a critical mediator of DR. Therefore, we investigated the effects of SC on diabetic retina by measuring VEGF levels. METHODS In this study, twenty-eight rats were divided into the following groups: group I, the control group; group II, rats with streptozotocin-induced diabetes; group III, rats with streptozotocin-induced diabetes receiving daily oral sildenafil at 1 mg/kg; and group IV, rats with streptozotocin-induced diabetes receiving high-dose daily sildenafil at 2.5 mg/kg. After 3 months, VEGF was measured in the retina specimen in one eye and the vitreous body in the other eye by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. RESULTS We found that VEGF expression in the retina was low in all rats from groups I and IV and in 30% of rats from group III; 80% of rats in group II demonstrated high VEGF expression in the retinae (P < 0.001). VEGF concentrations in the vitreous body samples were 32 ± 2, 61 ± 4, 44 ± 5, and 36 ± 3 pg/l in groups I-IV, respectively (P < 0.001). CONCLUSION VEGF decreased significantly in the eyes of diabetic rats after chronic oral sildenafil citrate treatment. SC may have a modifying/attenuating effect on DR. However, further studies are needed to evaluate its use as an adjunctive treatment.
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Affiliation(s)
- Osama A Sorour
- Department of Ophthalmology, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Elsayed Nassar
- Department of Ophthalmology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Naglaa Sarhan
- Department of Histology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Noha El-Anwar
- Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
- Department of Pathology, Armed Forces College of Medicine, Heliopolis, Egypt
| | - Reem A ElKholy
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
- Department of Pharmacology, School of medicine, Badr University, Badr, Egypt
| | - Dina M Tahoon
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Aalaa Sweilam
- Department of Ophthalmology, Faculty of Medicine, Tanta University, Tanta, Egypt
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dina Tadros
- Department of Ophthalmology, Faculty of Medicine, Tanta University, Tanta, Egypt
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Sun Z, Zou X, Bao M, Huang Z, Lou Y, Zhang Y, Huang P. Role of Ferroptosis in Fibrosis Diseases. Am J Med Sci 2023:S0002-9629(23)01174-6. [PMID: 37192694 DOI: 10.1016/j.amjms.2023.04.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 02/22/2023] [Accepted: 04/20/2023] [Indexed: 05/18/2023]
Abstract
Ferroptosis is a pervasive non-apoptotic mode of cell death that is different from autophagy or necrosis. It is mainly caused by an imbalance between the production and degradation of lipid reactive oxygen species in cells. Several metabolic pathways and biochemical processes, such as amino acid and lipid metabolism, iron handling, and mitochondrial respiration, affect and regulate cell sensitivity to peroxidation and ferroptosis. Organ fibrosis, a pathological manifestation of several etiological conditions, leads to chronic tissue injury and is characterized by excessive deposition of extracellular matrix components. Excessive tissue fibrosis can have diverse pathophysiological effects on several organ systems, eventually causing organ dysfunction and failure. The current manuscript provides a review that illustrates the link between ferroptosis and organ fibrosis and to better understand the underlying mechanisms. It provides novel potential therapeutic approaches and targets for fibrosis diseases.
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Affiliation(s)
- Zhiyong Sun
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaozhou Zou
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Meihua Bao
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Zhongjie Huang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yutao Lou
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou, China
| | - Yiwen Zhang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Ping Huang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
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Rogacka D, Rachubik P, Audzeyenka I, Kulesza T, Szrejder M, Myślińska D, Angielski S, Piwkowska A. Inhibition of phosphodiesterase 5A by tadalafil improves SIRT1 expression and activity in insulin-resistant podocytes. Cell Signal 2023; 105:110622. [PMID: 36754339 DOI: 10.1016/j.cellsig.2023.110622] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/13/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
A decrease in intracellular levels of 3',5'-cyclic guanosine monophosphate (cGMP) has been implicated in the progression of diabetic nephropathy. Hyperglycemia significantly inhibits cGMP-dependent pathway activity in the kidney, leading to glomerular damage and proteinuria. The enhancement of activity of this pathway that is associated with an elevation of cGMP levels may be achieved by inhibition of the cGMP specific phosphodiesterase 5A (PDE5A) using selective inhibitors, such as tadalafil. Hyperglycemia decreased the insulin responsiveness of podocytes and impaired podocyte function. These effects were associated with lower protein amounts and activity of the protein deacetylase sirtuin 1 (SIRT1) and a decrease in the phosphorylation of adenosine monophosphate-dependent protein kinase (AMPK). We found that PDE5A protein levels increased in hyperglycemia, and PDE5A downregulation improved the insulin responsiveness of podocytes with reestablished SIRT1 expression and activity. PDE5A inhibitors potentiate nitric oxide (NO)/cGMP signaling, and NO modulates the activity and expression of SIRT1. Therefore, we investigated the effects of tadalafil on SIRT1 and AMPK in the context of improving the insulin sensitivity in podocytes and podocyte function in hyperglycemia. Our study revealed that tadalafil restored SIRT1 expression and activity and activated AMPK by increasing its phosphorylation. Tadalafil also restored stimulating effect of insulin on glucose transport in podocytes with high glucose-induced insulin resistance. Additionally, tadalafil improved the function of podocytes that were exposed to high glucose concentrations. Our results display novel mechanisms involved in the pathogenesis of glomerulopathies in diabetes, which may contribute to the development of more effective treatment strategies for diabetic nephropathy.
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Affiliation(s)
- Dorota Rogacka
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza 63, Gdansk 80-308, Poland; Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, Gdansk 80-308, Poland.
| | - Patrycja Rachubik
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza 63, Gdansk 80-308, Poland.
| | - Irena Audzeyenka
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza 63, Gdansk 80-308, Poland; Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, Gdansk 80-308, Poland.
| | - Tomasz Kulesza
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza 63, Gdansk 80-308, Poland.
| | - Maria Szrejder
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza 63, Gdansk 80-308, Poland.
| | - Dorota Myślińska
- Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, Gdansk 80-308, Poland.
| | - Stefan Angielski
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza 63, Gdansk 80-308, Poland.
| | - Agnieszka Piwkowska
- Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza 63, Gdansk 80-308, Poland; Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, Gdansk 80-308, Poland.
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Fryk E, Rodrigues Silva VR, Bauzá-Thorbrügge M, Schmelz M, Gan LM, Strindberg L, Jansson PA. Feasibility of high-dose tadalafil and effects on insulin resistance in well-controlled patients with type 2 diabetes (MAKROTAD): a single-centre, double-blind, randomised, placebo-controlled, cross-over phase 2 trial. EClinicalMedicine 2023; 59:101985. [PMID: 37256099 PMCID: PMC10225663 DOI: 10.1016/j.eclinm.2023.101985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 06/01/2023] Open
Abstract
Background Phosphodiesterase-5 inhibitors exert positive vascular and metabolic effects in type 2 diabetes (T2D), but the effect on insulin resistance in T2D is unclear. Methods This randomised, double blind, placebo-controlled, two-period crossover trial was conducted at Sahlgrenska University Hospital (Gothenburg, Sweden). Men without apparent erectile dysfunction (age 40-70 years) and women (age 55-70 years, post-menopause) diagnosed with T2D between 3 months and 10 years, haemoglobin A1c (HbA1c) < 60 mmol/mol and a body mass index (BMI) 27-40 kg/m2 were enrolled. Participants were randomly assigned to one period of oral tadalafil 20 mg once a day and one period of placebo for 6 weeks, separated by an 8-week wash-out period. Placebo and tadalafil tablets were made visually indistinguishable and delivered randomized in two separate boxes for each participant. Both treatment periods ended with a glucose clamp, and measurements of body composition and metabolic markers in blood, subcutaneous and muscular interstitial fluid. The primary aim was to assess difference in whole-body insulin resistance after 6-weeks of treatment, determined after completion of the two study arms, and secondary aims were to study effects of tadalafil on pathophysiology of T2D as well as tolerability of high-dose tadalafil in T2D. Primary analysis was performed in participants with full analysis set (FAS) and safety analysis in all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT02601989), and EudraCT (2015-000573). Findings Between January 22nd, 2016, and January 31st, 2019, 23 participants with T2D were enrolled, of whom 18 were included in the full analysis set. The effect of tadalafil on insulin resistance was neutral compared with placebo. However, tadalafil decreased glycaemia measured as HbA1c (mean difference -2.50 mmol/mol, 95% confidence interval (CI), -4.20; -0.78, p = 0.005), and, further, we observed amelioration of endothelial function and markers of liver steatosis and glycolysis, whereas no statistically significant differences of other clinical phenotyping were shown. Muscle pain, dyspepsia, and headache were more frequent in participants on high-dose tadalafil compared with placebo (p < 0.05) but no difference between treatments appeared for serious adverse events. Interpretation High-dose tadalafil does not decrease whole-body insulin resistance, but increases microcirculation, induces positive effects in the liver and in intermediate metabolites, in parallel with an improved metabolic control measured as HbA1c. High-dose tadalafil is moderately well tolerated, warranting larger trials to define the optimal treatment regimen in T2D. Funding The Swedish Research Council, Swedish Diabetes Foundation, Novo Nordisk Foundation, the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement, Sahlgrenska University Hospital funds, Gothenburg Society of Medicine, Eli Lilly & Company, USA, and Eli Lilly & Company, Sweden AB.
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Affiliation(s)
- Emanuel Fryk
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SU Sahlgrenska, 413 45 Gothenburg, Sweden
| | - Vagner Ramon Rodrigues Silva
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SU Sahlgrenska, 413 45 Gothenburg, Sweden
| | - Marco Bauzá-Thorbrügge
- Department of Neuroscience and Physiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 430, 405 30 Gothenburg, Sweden
| | - Martin Schmelz
- Department of Anesthesiology and Intensive Care Medicine Mannheim, University of Heidelberg, 69117 Heidelberg, Germany
| | - Li-Ming Gan
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SU Sahlgrenska, 413 45 Gothenburg, Sweden
- Ribocure Pharmaceuticals AB, Sweden
- Suzhou Ribo Life Science CO. Ltd, China
| | - Lena Strindberg
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SU Sahlgrenska, 413 45 Gothenburg, Sweden
| | - Per-Anders Jansson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SU Sahlgrenska, 413 45 Gothenburg, Sweden
- Gothia Forum, Region Västra Götaland, SU Sahlgrenska, 413 45 Gothenburg, Sweden
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16
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Kukreja RC, Wang R, Koka S, Das A, Samidurai A, Xi L. Treating diabetes with combination of phosphodiesterase 5 inhibitors and hydroxychloroquine-a possible prevention strategy for COVID-19? Mol Cell Biochem 2023; 478:679-696. [PMID: 36036333 PMCID: PMC9421626 DOI: 10.1007/s11010-022-04520-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 06/30/2022] [Indexed: 01/09/2023]
Abstract
Type 2 diabetes (T2D) is one of the major risk factors for developing cardiovascular disease and the resultant devastating morbidity and mortality. The key features of T2D are hyperglycemia, hyperlipidemia, insulin resistance, and impaired insulin secretion. Patients with diabetes and myocardial infarction have worse prognosis than those without T2D. Moreover, obesity and T2D are recognized risk factors in developing severe form of COVID-19 with higher mortality rate. The current lines of drug therapy are insufficient to control T2D and its serious cardiovascular complications. Phosphodiesterase 5 (PDE5) is a cGMP specific enzyme, which is the target of erectile dysfunction drugs including sildenafil, vardenafil, and tadalafil. Cardioprotective effects of PDE5 inhibitors against ischemia/reperfusion (I/R) injury were reported in normal and diabetic animals. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug and its hyperglycemia-controlling effect in diabetic patients is also under investigation. This review provides our perspective of a potential use of combination therapy of PDE5 inhibitor with HCQ to reduce cardiovascular risk factors and myocardial I/R injury in T2D. We previously observed that diabetic mice treated with tadalafil and HCQ had significantly reduced fasting blood glucose and lipid levels, increased plasma insulin and insulin-like growth factor-1 levels, and improved insulin sensitivity, along with smaller myocardial infarct size following I/R. The combination treatment activated Akt/mTOR cellular survival pathway, which was likely responsible for the salutary effects. Therefore, pretreatment with PDE5 inhibitor and HCQ may be a potentially useful therapy not only for controlling T2D but also reducing the rate and severity of COVID-19 infection in the vulnerable population of diabetics.
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Affiliation(s)
- Rakesh C Kukreja
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA, 23298-0204, USA.
| | - Rui Wang
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA, 23298-0204, USA
| | - Saisudha Koka
- Department of Microbiology, Immunology and Pharmacology, Arkansas College of Osteopathic Medicine, Fort Smith, AR, 72916-6024, USA
| | - Anindita Das
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA, 23298-0204, USA
| | - Arun Samidurai
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA, 23298-0204, USA
| | - Lei Xi
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA, 23298-0204, USA.
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Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure. Nat Rev Cardiol 2023; 20:90-108. [PMID: 36050457 DOI: 10.1038/s41569-022-00756-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2022] [Indexed: 01/21/2023]
Abstract
Cyclic nucleotide phosphodiesterases (PDEs) modulate the neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple PDE isozymes with different enzymatic properties and subcellular localization regulate local pools of cyclic nucleotides and specific functions. This organization is heavily perturbed during cardiac hypertrophy and heart failure (HF), which can contribute to disease progression. Clinically, PDE inhibition has been considered a promising approach to compensate for the catecholamine desensitization that accompanies HF. Although PDE3 inhibitors, such as milrinone or enoximone, have been used clinically to improve systolic function and alleviate the symptoms of acute HF, their chronic use has proved to be detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as new potential targets to treat HF, each having a unique role in local cyclic nucleotide signalling pathways. In this Review, we describe cAMP and cGMP signalling in cardiomyocytes and present the various PDE families expressed in the heart as well as their modifications in pathological cardiac hypertrophy and HF. We also appraise the evidence from preclinical models as well as clinical data pointing to the use of inhibitors or activators of specific PDEs that could have therapeutic potential in HF.
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18
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Swiecicka A. The efficacy of PDE5 inhibitors in diabetic patients. Andrology 2023; 11:245-256. [PMID: 36367281 PMCID: PMC10107754 DOI: 10.1111/andr.13328] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 09/27/2022] [Accepted: 10/14/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND Phosphodiesterase 5 inhibitors (PDE5i), since their introduction in the late 1990s, have proven their efficacy in treating several conditions, predominantly pulmonary hypertension and erectile dysfunction where they remain the first-line therapeutic option. However, in the recent years, growing evidence from both animal and human studies has emerged to suggest the additional benefits of PDE5i in cardiovascular and metabolic disorders. This is of specific interest to the diabetes population where prevalent cardiovascular disease and metabolic dysregulation significantly contribute to the increased morbidity and mortality. OBJECTIVES To examine the available data on the non-standard, pleiotropic effects of PDE5i in patients with diabetes mellitus. MATERIALS AND METHODS The review of the published background research, preclinical studies and clinical trials. RESULTS In human studies, PDE5 inhibition appeared to be associated with reduced cardiovascular mortality and overall improved clinical outcomes in those with established cardiovascular disease. PDE5i were also consistently found to reduce albuminuria in subjects with diabetic nephropathy. Furthermore, animal data suggest a plausible effect of this group of medication on sensory function and neuropathic symptoms in diabetic neuropathy as well as improved wound healing. A decrease in insulin resistance and augmentation of beta cell function seen in preclinical studies has not been consistently demonstrated in human trials. DISCUSSION AND CONCLUSION In animal models, PDE5 inhibition appears to decrease oxidative stress and reduce some of the micro- and macrovascular complications associated with diabetes. However, data from human trials are limited and largely inconsistent, highlighting the need for adequately powered, randomised-controlled trials in diabetic cohorts in order to fully assess the benefits of PDE5i in this group of patients.
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Affiliation(s)
- Agnieszka Swiecicka
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus
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19
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Samidurai A, Xi L, Das A, Kukreja RC. Beyond Erectile Dysfunction: cGMP-Specific Phosphodiesterase 5 Inhibitors for Other Clinical Disorders. Annu Rev Pharmacol Toxicol 2023; 63:585-615. [PMID: 36206989 DOI: 10.1146/annurev-pharmtox-040122-034745] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation of the soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain urological disorders. Preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, heart failure, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, and other aging-related conditions. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular, anticancer, and neurological benefits. In this review, we provide an overview of the current state of knowledge on PDE5 inhibitors and their potential therapeutic indications for various clinical disorders beyond erectile dysfunction.
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Affiliation(s)
- Arun Samidurai
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
| | - Lei Xi
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
| | - Anindita Das
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
| | - Rakesh C Kukreja
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA;
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20
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Structural Characterization of Murine Phosphodiesterase 5 Isoforms and Involvement of Cysteine Residues in Supramolecular Assembly. Int J Mol Sci 2023; 24:ijms24021108. [PMID: 36674621 PMCID: PMC9862819 DOI: 10.3390/ijms24021108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/22/2022] [Accepted: 12/24/2022] [Indexed: 01/09/2023] Open
Abstract
Phosphodiesterases (PDEs) are a superfamily of evolutionarily conserved cyclic nucleotide (cAMP/cGMP)-hydrolyzing enzymes, components of transduction pathways regulating crucial aspects of cell life. Within this family, the cGMP-dependent PDE5 is the major hydrolyzing enzyme in many mammalian tissues, where it regulates a number of cellular and tissular processes. Using Kluyveromyces lactis as a model organism, the murine PDE5A1, A2 and A3 isoforms were successfully expressed and studied, evidencing, for the first time, a distinct role of each isoform in the control, modulation and maintenance of the cellular redox metabolism. Moreover, we demonstrated that the short N-terminal peptide is responsible for the tetrameric assembly of MmPDE5A1 and for the mitochondrial localization of MmPDE5A2. We also analyzed MmPDE5A1, A2 and A3 using small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), structural mass spectrometry (MS) and polyacrylamide gel electrophoresis in their native conditions (native-PAGE) and in the presence of redox agents. These analyses pointed towards the role of a few specific cysteines in the isoforms' oligomeric assembly and the loss of enzymatic activity when modified.
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Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology. Int J Mol Sci 2022; 24:ijms24010703. [PMID: 36614143 PMCID: PMC9820699 DOI: 10.3390/ijms24010703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/20/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Phosphodiesterase 5A (PDE5A) is involved in cGMP hydrolysis, regulating many physiological processes. Increased activity of PDE5A has been found in several pathological conditions, and the pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications. We have identified the presence of three different Pde5a isoforms in cardiomyocytes, and we have found that the expression of specific Pde5a isoforms may have a causal role in the onset of pathological responses in these cells. In our previous study, we demonstrated that PDE5A inhibition could ameliorate muscular dystrophy by acting at different levels, as assessed by the altered genomic response of muscular cells following treatment with the PDE5A inhibitor tadalafil. Thus, considering the importance of PDE5A in various pathophysiological conditions, we further investigated the regulation of this enzyme. Here, we analysed the expression of Pde5a isoforms in the pathophysiology of skeletal muscle. We found that skeletal muscle tissues and myogenic cells express Pde5a1 and Pde5a2 isoforms, and we observed an increased expression of Pde5a1 in damaged skeletal muscles, while Pde5a2 levels remained unchanged. We also cloned and characterized the promoters that control the transcription of Pde5a isoforms, investigating which of the transcription factors predicted by bioinformatics analysis could be involved in their modulation. In conclusion, we found an overexpression of Pde5a1 in compromised muscle and identified an involvement of MyoD and Runx1 in Pde5a1 transcriptional activity.
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22
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Suffredini G, Slowey C, Sun J, Gao WD, Choi CDW, Aziz H, Kilic A, Schena S, Lawton J, Hamilton JP, Dodd-O JM. Preoperative Liver Stiffness is Associated With Hospital Length of Stay After Cardiac Surgery. J Cardiothorac Vasc Anesth 2022; 36:4093-4099. [PMID: 35915004 DOI: 10.1053/j.jvca.2022.06.028] [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] [Received: 05/09/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 11/11/2022]
Abstract
OBJECTIVES Risk assessment models for cardiac surgery do not account for the degrees of liver dysfunction. Ultrasound shear-wave elastography measures liver stiffness (LSM), a quantitative measurement related to fibrosis, congestion, and inflammation. The authors hypothesized that preoperative liver stiffness would be associated with hospital length of stay after cardiac surgery. DESIGN Prospective observational study. SETTING University hospital, single center. PARTICIPANTS One hundred five adult patients undergoing nonemergent cardiac surgery. INTERVENTIONS Preoperative liver stiffness measured by ultrasound elastography. MEASUREMENTS AND MAIN RESULTS The associations were analyzed using linear mixed models, with adjustments for preoperative variables, duration of cardiopulmonary bypass, and type of surgery. Median liver stiffness was 6.4 kPa (range, 4.1-18.6 kPa). The median length of hospital stay was 6 days (range, 3-18 d). Each unit increase in liver stiffness, treated as a continuous variable, was associated with an increase of 0.32 ± 0.10 days in the hospital (p = 0.002). When treated as a categorical variable (<6 kPa, 6-9.4 kPa, and ≥9.5 kPa), LSM ≥9.5 kPa v LSM <6 kPa was associated strongly with an increase in hospital length of stay of 3.25 ± 0.87 days (p = 0.0003). CONCLUSIONS A preoperative LSM ≥9.5 kPa was associated with a significantly longer postoperative hospital length of stay. This association appeared independent of preoperative comorbidities commonly associated with coronary disease. Preoperative liver stiffness is a novel risk metric that is associated with the postoperative hospital length of stay after cardiac surgery.
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Affiliation(s)
- Giancarlo Suffredini
- Department of Anesthesiology and Critical Care Medicine, Division of Cardiac Anesthesia Johns Hopkins University School of Medicine, Baltimore, MD.
| | - Charlie Slowey
- Department of Anesthesiology and Critical Care Medicine, Division of Cardiac Anesthesia Johns Hopkins University School of Medicine, Baltimore, MD
| | - Junfeng Sun
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Wei Dong Gao
- Department of Anesthesiology and Critical Care Medicine, Division of Cardiac Anesthesia Johns Hopkins University School of Medicine, Baltimore, MD
| | - Chun Dan W Choi
- Department of Surgery, Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore MD
| | - Hamza Aziz
- Department of Surgery, Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore MD
| | - Ahmet Kilic
- Department of Surgery, Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore MD
| | - Stefano Schena
- Department of Surgery, Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore MD
| | - Jennifer Lawton
- Department of Surgery, Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore MD
| | - James Peter Hamilton
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jeffrey M Dodd-O
- Department of Anesthesiology and Critical Care Medicine, Division of Cardiac Anesthesia Johns Hopkins University School of Medicine, Baltimore, MD
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Chen Y, Yang F, Chu Y, Yun Z, Yan Y, Jin J. Mitochondrial transplantation: opportunities and challenges in the treatment of obesity, diabetes, and nonalcoholic fatty liver disease. Lab Invest 2022; 20:483. [PMID: 36273156 PMCID: PMC9588235 DOI: 10.1186/s12967-022-03693-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022]
Abstract
Metabolic diseases, including obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD), are rising in both incidence and prevalence and remain a major global health and socioeconomic burden in the twenty-first century. Despite an increasing understanding of these diseases, the lack of effective treatments remains an ongoing challenge. Mitochondria are key players in intracellular energy production, calcium homeostasis, signaling, and apoptosis. Emerging evidence shows that mitochondrial dysfunction participates in the pathogeneses of metabolic diseases. Exogenous supplementation with healthy mitochondria is emerging as a promising therapeutic approach to treating these diseases. This article reviews recent advances in the use of mitochondrial transplantation therapy (MRT) in such treatment.
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Affiliation(s)
- Yifei Chen
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.,School of Medicine, Jiangsu University, ZhenjiangJiangsu Province, 212013, China
| | - Fuji Yang
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.,School of Medicine, Jiangsu University, ZhenjiangJiangsu Province, 212013, China
| | - Ying Chu
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.,Central Laboratory, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China
| | - Zhihua Yun
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China. .,Central Laboratory, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.
| | - Jianhua Jin
- Department of Oncology, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.
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Wang S, Tian C, Gao Z, Zhang B, Zhao L. Research status and trends of the diabetic cardiomyopathy in the past 10 years (2012–2021): A bibliometric analysis. Front Cardiovasc Med 2022; 9:1018841. [PMID: 36337893 PMCID: PMC9630656 DOI: 10.3389/fcvm.2022.1018841] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 09/28/2022] [Indexed: 11/28/2022] Open
Abstract
Background Diabetic cardiomyopathy is one of the most life-threatening diabetic complications. However, the previous studies only discuss a particular aspect or characteristic of DCM, the current state and trends were explored by limited research. We aimed to perform a systemically bibliometric study of DCM research progress status in the past decade, visualize the internal conceptual structure and potential associations, and further explore the prospective study trends. Methods Articles related to DCM published from January 2012 to December 2021 were collected in the Web of Science core collection (WoSCC) database on June 24, 2022. We exported all bibliographic records, including titles, abstracts, keywords, authorship, institutions, addresses, publishing sources, references, citation times, and year of publication. In addition, the journal Impact Factor and Hirsch index were obtained from the Journal Citation Report. We conducted the data screening, statistical analysis, and visualization via the Bibliometrix R package. VOS viewer software was employed to generate the collaboration network map among countries and institutions for better performance in visualization. Results In total, 1,887 original research articles from 2012 to 2021 were identified. The number of annual publications rapidly increased from 107 to 278, and a drastic increase in citation times was observed in 2017–2019. As for global contributions, the United States was the most influential country with the highest international collaboration, while China was the most productive country. Professor Cai Lu was the most prolific author. Shandong University published the most articles. Cardiovascular Diabetology journal released the most DCM-related articles. “Metabolic Stress-induced Activation of FoxO1 Triggers Diabetic Cardiomyopathy in Mice” Battiprolu PK et al., J Clin Invest, 2012. was the most top-cited article regarding local citations. The top three keywords in terms of frequency were apoptosis, oxidative stress, and fibrosis. The analysis of future topic trends indicated that “Forkhead box protein O1,” “Heart failure with preserved ejection fraction,” “Dapagliflozin,” “Thioredoxin,” “Mitochondria dysfunction,” “Glucose,” “Pyroptosis,” “Cardiac fibroblast” and “Long non-coding RNA” could be promising hotspots. Conclusion This study provides meaningful insights into DCM, which is expected to assist cardiologists and endocrinologists in exploring frontiers and future research directions in the domain through a refined and concise summary.
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Affiliation(s)
- Sicheng Wang
- Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chuanxi Tian
- Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Zezheng Gao
- Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Boxun Zhang
- Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Boxun Zhang,
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Linhua Zhao,
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Schmitz T, Harmel E, Heier M, Peters A, Linseisen J, Meisinger C. Inflammatory plasma proteins predict short-term mortality in patients with an acute myocardial infarction. J Transl Med 2022; 20:457. [PMID: 36209229 PMCID: PMC9547640 DOI: 10.1186/s12967-022-03644-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/18/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the association between inflammatory markers and 28-day mortality in patients with ST-elevation myocardial infarction (STEMI). METHODS In 398 STEMI patients recorded between 2009 and 2013 by the population-based Myocardial Infarction Registry Augsburg, 92 protein biomarkers were measured in admission arterial blood samples using the OLINK inflammatory panel. In multivariable-adjusted logistic regression models, the association between each marker and 28-day mortality was investigated. The values of the biomarkers most significantly associated with mortality were standardized and summarized to obtain a prediction score for 28-day mortality. The predictive ability of this biomarker score was compared to the established GRACE score using ROC analysis. Finally, a combined total score was generated by adding the standardized biomarker score to the standardized GRACE score. RESULTS The markers IL-6, IL-8, IL-10, FGF-21, FGF-23, ST1A1, MCP-1, 4E-BP1, and CST5 were most significantly associated with 28-day mortality, each with FDR-adjusted (false discovery rate adjusted) p-values of < 0.01 in the multivariable logistic regression model. In a ROC analysis, the biomarker score and the GRACE score showed comparable predictive ability for 28-day mortality (biomarker score AUC: 0.7859 [CI: 0.6735-0.89], GRACE score AUC: 0.7961 [CI: 0.6965-0.8802]). By combining the biomarker score and the Grace score, the predictive ability improved with an AUC of 0.8305 [CI: 0.7269-0.9187]. A continuous Net Reclassification Improvement (cNRI) of 0.566 (CI: 0.192-0.94, p-value: 0.003) and an Integrated Discrimination Improvement (IDI) of 0.083 ((CI: 0.016-0.149, p-value: 0.015) confirmed the superiority of the combined score over the GARCE score. CONCLUSIONS Inflammatory biomarkers may play a significant role in the pathophysiology of acute myocardial infarction (AMI) and AMI-related mortality and might be a promising starting point for personalized medicine, which aims to provide each patient with tailored therapy.
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Affiliation(s)
- T. Schmitz
- grid.419801.50000 0000 9312 0220Epidemiology, Medical Faculty, University of Augsburg, University Hospital Augsburg, Stenglinstraße 2, 86156 Augsburg, Germany
| | - E. Harmel
- grid.419801.50000 0000 9312 0220Department of Cardiology, Respiratory Medicine and Intensive Care, University Hospital Augsburg, Augsburg, Germany
| | - M. Heier
- grid.419801.50000 0000 9312 0220University Hospital of Augsburg, KORA Study Centre, Augsburg, Germany ,Helmholtz Zentrum München, Institute for Epidemiology, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - A. Peters
- Helmholtz Zentrum München, Institute for Epidemiology, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany ,grid.5252.00000 0004 1936 973XChair of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany ,grid.452622.5German Center for Diabetes Research (DZD), Neuherberg, Germany ,grid.452396.f0000 0004 5937 5237German Research Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - J. Linseisen
- grid.419801.50000 0000 9312 0220Epidemiology, Medical Faculty, University of Augsburg, University Hospital Augsburg, Stenglinstraße 2, 86156 Augsburg, Germany
| | - C. Meisinger
- grid.419801.50000 0000 9312 0220Epidemiology, Medical Faculty, University of Augsburg, University Hospital Augsburg, Stenglinstraße 2, 86156 Augsburg, Germany
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Nutraceutical Prevention of Diabetic Complications—Focus on Dicarbonyl and Oxidative Stress. Curr Issues Mol Biol 2022; 44:4314-4338. [PMID: 36135209 PMCID: PMC9498143 DOI: 10.3390/cimb44090297] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/25/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Oxidative and dicarbonyl stress, driven by excess accumulation of glycolytic intermediates in cells that are highly permeable to glucose in the absence of effective insulin activity, appear to be the chief mediators of the complications of diabetes. The most pathogenically significant dicarbonyl stress reflects spontaneous dephosphorylation of glycolytic triose phosphates, giving rise to highly reactive methylglyoxal. This compound can be converted to harmless lactate by the sequential activity of glyoxalase I and II, employing glutathione as a catalyst. The transcription of glyoxalase I, rate-limiting for this process, is promoted by Nrf2, which can be activated by nutraceutical phase 2 inducers such as lipoic acid and sulforaphane. In cells exposed to hyperglycemia, glycine somehow up-regulates Nrf2 activity. Zinc can likewise promote glyoxalase I transcription, via activation of the metal-responsive transcription factor (MTF) that binds to the glyoxalase promoter. Induction of glyoxalase I and metallothionein may explain the protective impact of zinc in rodent models of diabetic complications. With respect to the contribution of oxidative stress to diabetic complications, promoters of mitophagy and mitochondrial biogenesis, UCP2 inducers, inhibitors of NAPDH oxidase, recouplers of eNOS, glutathione precursors, membrane oxidant scavengers, Nrf2 activators, and correction of diabetic thiamine deficiency should help to quell this.
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27
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Ovchinnikov A, Potekhina A, Belyavskiy E, Ageev F. Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors. Pharmaceuticals (Basel) 2022; 15:ph15081024. [PMID: 36015172 PMCID: PMC9414416 DOI: 10.3390/ph15081024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/17/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, "precapillary" alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment.
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Affiliation(s)
- Artem Ovchinnikov
- Out-Patient Department, Institute of Clinical Cardiology, National Medical Research Center of Cardiology Named after Academician E.I. Chazov, 3-d Cherepkovskaya St., 15a, 121552 Moscow, Russia
- Department of Clinical Functional Diagnostics, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Delegatskaya St., 20, p. 1, 127473 Moscow, Russia
- Correspondence: ; Tel.: +7-(495)-414-66-12 or +7-(916)-505-79-58; Fax: +7-(495)-414-66-12
| | - Alexandra Potekhina
- Out-Patient Department, Institute of Clinical Cardiology, National Medical Research Center of Cardiology Named after Academician E.I. Chazov, 3-d Cherepkovskaya St., 15a, 121552 Moscow, Russia
| | - Evgeny Belyavskiy
- Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Augustenburger Platz, 13353 Berlin, Germany
| | - Fail Ageev
- Out-Patient Department, Institute of Clinical Cardiology, National Medical Research Center of Cardiology Named after Academician E.I. Chazov, 3-d Cherepkovskaya St., 15a, 121552 Moscow, Russia
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Li SY, Chen S, Lu XT, Fang AP, Chen YM, Huang RZ, Lin XL, Huang ZH, Ma JF, Huang BX, Zhu HL. Serum trimethylamine-N-oxide is associated with incident type 2 diabetes in middle-aged and older adults: a prospective cohort study. Lab Invest 2022; 20:374. [PMID: 35982495 PMCID: PMC9389664 DOI: 10.1186/s12967-022-03581-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/07/2022] [Indexed: 11/17/2022]
Abstract
Background The role of trimethylamine-N-oxide (TMAO) in the development of diabetes remains controversial, and prospective data are few. We aimed to investigate the association between serum TMAO and incident type 2 diabetes in middle-aged and older adults. Methods This study was based on the Guangzhou Nutrition and Health Study (GNHS), a community-based prospective cohort study in China. A total of 2088 diabetes-free participants aged 40–75 years were included from 2008 to 2010. Incident type 2 diabetes was ascertained during follow-up visits. Baseline serum TMAO was measured by high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for diabetes across tertiles of serum TMAO were calculated using Cox proportional hazard models. Prospective associations of serum TMAO with changes in glycemic traits (fasting glucose, HbA1c, insulin, HOMA-IR) over time were estimated using linear mixed-effects models (LMEMs). Results We ascertained 254 incident type 2 diabetes cases during a median follow-up of 8.9 years. The median (interquartile range) of serum TMAO was 1.54 (0.86–2.91) μmol/L. From the first to the third tertile of serum TMAO, the multivariable-adjusted HRs for diabetes were 1.00 (reference), 1.17 (95% CI: 0.84–1.61), and 1.42 (95% CI: 1.03–1.96) (P-trend = 0.031). LMEMs showed that the estimated yearly change in fasting glucose was 0.011 (0.001–0.022) mmol/L/y in the highest tertile of serum TMAO, compared with the lowest tertile (P-interaction = 0.044). Serum TMAO was not associated with longitudinal changes in HbA1c, insulin or HOMA-IR. Conclusions Our findings suggested that higher serum TMAO was associated with a higher risk of type 2 diabetes and an increase in fasting glucose among middle-aged and older Chinese adults. Trial registration: NCT03179657. https://clinicaltrials.gov/ct2/show/NCT03179657?term=NCT03179657&draw=2&rank=1 Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03581-7.
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Affiliation(s)
- Shu-Yi Li
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Si Chen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Xiao-Ting Lu
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Ai-Ping Fang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yu-Ming Chen
- Department of Medical Statistics & Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Rong-Zhu Huang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Xin-Lei Lin
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Zi-Hui Huang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Jing-Fei Ma
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Bi-Xia Huang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.
| | - Hui-Lian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China. .,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China.
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Cardarelli S, Miele AE, Campolo F, Massimi M, Mancini P, Biagioni S, Naro F, Giorgi M, Saliola M. Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms. Int J Mol Sci 2022; 23:ijms23158587. [PMID: 35955722 PMCID: PMC9368758 DOI: 10.3390/ijms23158587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/18/2022] [Accepted: 07/29/2022] [Indexed: 11/16/2022] Open
Abstract
3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionarily conserved cAMP and/or cGMP hydrolyzing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5—being a regulator of vascular smooth muscle contraction—is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension. Production of full-length murine PDE5A isoforms in the milk-yeast Kluyveromyces lactis showed that the quaternary assembly of MmPDE5A1 is a mixture of dimers and tetramers, while MmPDE5A2 and MmPDE5A3 only assembled as dimers. We showed that the N-terminal peptide is responsible for the tetramer assembly of MmPDE5A1, while that of the MmPDE5A2 is responsible for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)+/NAD(P)H balance and induces a metabolic switch from oxidative to fermentative. In particular, the mitochondrial localization of MmPDE5A2 unveiled the existence of a cAMP-cGMP signaling cascade in this organelle, for which we propose a metabolic model that could explain the role of PDE5 in some cardiomyopathies and some of the side effects of its inhibitors.
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Affiliation(s)
- Silvia Cardarelli
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy; (S.C.); (S.B.); (M.S.)
| | - Adriana Erica Miele
- Department of Biochemical Sciences, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy
- UMR 5280 ISA-CNRS-UCBL, Université de Lyon, 5 Rue de La Doua, 69100 Villeurbanne, France
- Correspondence: (A.E.M.); (M.G.)
| | - Federica Campolo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (F.C.); (P.M.)
| | - Mara Massimi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy;
| | - Patrizia Mancini
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (F.C.); (P.M.)
| | - Stefano Biagioni
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy; (S.C.); (S.B.); (M.S.)
| | - Fabio Naro
- Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Sapienza University of Rome, Via A. Borelli 50, 00161 Rome, Italy;
| | - Mauro Giorgi
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy; (S.C.); (S.B.); (M.S.)
- Correspondence: (A.E.M.); (M.G.)
| | - Michele Saliola
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy; (S.C.); (S.B.); (M.S.)
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Targeting Myocardial Fibrosis—A Magic Pill in Cardiovascular Medicine? Pharmaceutics 2022; 14:pharmaceutics14081599. [PMID: 36015225 PMCID: PMC9414721 DOI: 10.3390/pharmaceutics14081599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/16/2022] Open
Abstract
Fibrosis, characterized by an excessive accumulation of extracellular matrix, has long been seen as an adaptive process that contributes to tissue healing and regeneration. More recently, however, cardiac fibrosis has been shown to be a central element in many cardiovascular diseases (CVDs), contributing to the alteration of cardiac electrical and mechanical functions in a wide range of clinical settings. This paper aims to provide a comprehensive review of cardiac fibrosis, with a focus on the main pathophysiological pathways involved in its onset and progression, its role in various cardiovascular conditions, and on the potential of currently available and emerging therapeutic strategies to counteract the development and/or progression of fibrosis in CVDs. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research.
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Petraina A, Nogales C, Krahn T, Mucke H, Lüscher TF, Fischmeister R, Kass DA, Burnett JC, Hobbs AJ, Schmidt HHHW. Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology. Cardiovasc Res 2022; 118:2085-2102. [PMID: 34270705 PMCID: PMC9302891 DOI: 10.1093/cvr/cvab240] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 07/14/2021] [Indexed: 12/13/2022] Open
Abstract
Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3'-5'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.
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Affiliation(s)
- Alexandra Petraina
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Cristian Nogales
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Thomas Krahn
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Hermann Mucke
- H.M. Pharma Consultancy, Enenkelstrasse 28/32, A-1160, Vienna, Austria
| | - Thomas F Lüscher
- Royal Brompton & Harefield Hospitals, Heart Division and National Heart and Lung Institute, Guy Scadding Building, Imperial College, Dovehouse Street London SW3 6LY, United Kingdom
- Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistreet 12, CH-8952 Schlieren, Switzerland
| | - Rodolphe Fischmeister
- INSERM UMR-S 1180, Faculty of Pharmacy, Université Paris-Saclay, F-92296 Châtenay-Malabry, France
| | - David A Kass
- Division of Cardiology, Department of Medicine, Ross Research Building, Rm 858, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA
| | - John C Burnett
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
| | - Adrian J Hobbs
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, UK
| | - Harald H H W Schmidt
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
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Epicardial Adipose Tissue: A Novel Potential Imaging Marker of Comorbidities Caused by Chronic Inflammation. Nutrients 2022; 14:nu14142926. [PMID: 35889883 PMCID: PMC9316118 DOI: 10.3390/nu14142926] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 07/09/2022] [Indexed: 12/11/2022] Open
Abstract
The observation of correlations between obesity and chronic metabolic and cardiovascular diseases has led to the emergence of strong interests in “adipocyte biology”, in particular in relation to a specific visceral adipose tissue that is the epicardial adipose tissue (EAT) and its pro-inflammatory role. In recent years, different imaging techniques frequently used in daily clinical practice have tried to obtain an EAT quantification. We provide a useful update on comorbidities related to chronic inflammation typical of cardiac adiposity, analyzing how the EAT assessment could impact and provide data on the patient prognosis. We assessed for eligibility 50 papers, with a total of 10,458 patients focusing the review on the evaluation of EAT in two main contexts: cardiovascular and metabolic diseases. Given its peculiar properties and rapid responsiveness, EAT could act as a marker to investigate the basal risk factor and follow-up conditions. In the future, EAT could represent a therapeutic target for new medications. The assessment of EAT should become part of clinical practice to help clinicians to identify patients at greater risk of developing cardiovascular and/or metabolic diseases and to provide information on their clinical and therapeutic outcomes.
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33
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The Role of Mitochondria in Metabolic Syndrome–Associated Cardiomyopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9196232. [PMID: 35783195 PMCID: PMC9246605 DOI: 10.1155/2022/9196232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/12/2022] [Accepted: 06/13/2022] [Indexed: 12/03/2022]
Abstract
With the rapid development of society, the incidence of metabolic syndrome (MS) is increasing rapidly. Evidence indicated that patients diagnosed with MS usually suffered from cardiomyopathy, called metabolic syndrome–associated cardiomyopathy (MSC). The clinical characteristics of MSC included cardiac hypertrophy and diastolic dysfunction, followed by heart failure. Despite many studies on this topic, the detailed mechanisms are not clear yet. As the center of cellular metabolism, mitochondria are crucial for maintaining heart function, while mitochondria dysfunction plays a vital role through mechanisms such as mitochondrial energy deprivation, calcium disorder, and ROS (reactive oxygen species) imbalance during the development of MSC. Accordingly, in this review, we will summarize the characteristics of MSC and especially focus on the mechanisms related to mitochondria. In addition, we will update new therapeutic strategies in this field.
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34
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Pofi R, Giannetta E, Feola T, Galea N, Barbagallo F, Campolo F, Badagliacca R, Barbano B, Ciolina F, Defeudis G, Filardi T, Sesti F, Minnetti M, Vizza CD, Pasqualetti P, Caboni P, Carbone I, Francone M, Catalano C, Pozzilli P, Lenzi A, Venneri MA, Gianfrilli D, Isidori AM. Sex-specific effects of daily tadalafil on diabetic heart kinetics in RECOGITO, a randomized, double-blind, placebo-controlled trial. Sci Transl Med 2022; 14:eabl8503. [PMID: 35704597 DOI: 10.1126/scitranslmed.abl8503] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (-3.40°, -5.96; -0.84, P = 0.011) and fiber shortening (-1.19%, -2.24; -0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14++CD16- monocytes reduced, and Tie2+ monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.
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Affiliation(s)
- Riccardo Pofi
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Tiziana Feola
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.,Neuroendocrinology, Neuromed Institute, IRCCS, 86077 Pozzilli (IS), Italy
| | - Nicola Galea
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Federica Barbagallo
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Federica Campolo
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Roberto Badagliacca
- Department of Cardiovascular and Respiratory Diseases, Sapienza University of Rome, 00161 Rome, Italy
| | - Biagio Barbano
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Federica Ciolina
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, 00161 Rome, Italy
| | - Giuseppe Defeudis
- Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, 00161 Rome, Italy
| | - Tiziana Filardi
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Marianna Minnetti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Carmine D Vizza
- Department of Cardiovascular and Respiratory Diseases, Sapienza University of Rome, 00161 Rome, Italy
| | - Patrizio Pasqualetti
- Medical Statistics and Information Technology, AFaR, Fatebenefratelli Hospital, 00161 Rome, Italy
| | - Pierluigi Caboni
- Department of Life and Environmental Sciences, University of Cagliari, 09124 Cagliari, Italy
| | - Iacopo Carbone
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Francone
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, 00161 Rome, Italy
| | - Carlo Catalano
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, 00161 Rome, Italy
| | - Paolo Pozzilli
- Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, 00161 Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Mary Anna Venneri
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Daniele Gianfrilli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
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Rocca A, van Heeswijk RB, Richiardi J, Meyer P, Hullin R. The Cardiomyocyte in Heart Failure with Preserved Ejection Fraction-Victim of Its Environment? Cells 2022; 11:867. [PMID: 35269489 PMCID: PMC8909081 DOI: 10.3390/cells11050867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/01/2022] [Indexed: 12/07/2022] Open
Abstract
Heart failure (HF) with preserved left ventricular ejection fraction (HFpEF) is becoming the predominant form of HF. However, medical therapy that improves cardiovascular outcome in HF patients with almost normal and normal systolic left ventricular function, but diastolic dysfunction is missing. The cause of this unmet need is incomplete understanding of HFpEF pathophysiology, the heterogeneity of the patient population, and poor matching of therapeutic mechanisms and primary pathophysiological processes. Recently, animal models improved understanding of the pathophysiological role of highly prevalent and often concomitantly presenting comorbidity in HFpEF patients. Evidence from these animal models provide first insight into cellular pathophysiology not considered so far in HFpEF disease, promising that improved understanding may provide new therapeutical targets. This review merges observation from animal models and human HFpEF disease with the intention to converge cardiomyocytes pathophysiological aspects and clinical knowledge.
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Affiliation(s)
- Angela Rocca
- Department of Cardiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland;
| | - Ruud B. van Heeswijk
- Department of Diagnostic and Interventional Radiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland; (R.B.v.H.); (J.R.)
| | - Jonas Richiardi
- Department of Diagnostic and Interventional Radiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland; (R.B.v.H.); (J.R.)
| | - Philippe Meyer
- Cardiology Service, Department of Medical Specialties, Faculty of Science, Geneva University Hospital, University of Geneva, 1205 Geneva, Switzerland;
| | - Roger Hullin
- Department of Cardiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland;
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36
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Zheng Z, Hua R, Xu G, Yang H, Shi P. Gene losses may contribute to subterranean adaptations in naked mole-rat and blind mole-rat. BMC Biol 2022; 20:44. [PMID: 35172813 PMCID: PMC8851862 DOI: 10.1186/s12915-022-01243-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/28/2022] [Indexed: 01/18/2023] Open
Abstract
Background Naked mole-rats (Heterocephalus glaber, NMRs) and blind mole-rats (Spalax galili, BMRs) are representative subterranean rodents that have evolved many extraordinary traits, including hypoxia tolerance, longevity, and cancer resistance. Although multiple candidate loci responsible for these traits have been uncovered by genomic studies, many of them are limited to functional changes to amino acid sequence and little is known about the contributions of other genetic events. To address this issue, we focused on gene losses (unitary pseudogenes) and systematically analyzed gene losses in NMRs and BMRs, aiming to elucidate the potential roles of pseudogenes in their adaptation to subterranean lifestyle. Results We obtained the pseudogene repertoires in NMRs and BMRs, as well as their respective aboveground relatives, guinea pigs and rats, on a genome-wide scale. As a result, 167, 139, 341, and 112 pseudogenes were identified in NMRs, BMRs, guinea pigs, and rats, respectively. Functional enrichment analysis identified 4 shared and 2 species-specific enriched functional groups (EFGs) in subterranean lineages. Notably, the pseudogenes in these EFGs might be associated with either regressive (e.g., visual system) or adaptive (e.g., altered DNA damage response) traits. In addition, several pseudogenes including TNNI3K and PDE5A might be associated with specific cardiac features observed in subterranean lineages. Interestingly, we observed 20 convergent gene losses in NMRs and BMRs. Given that the functional investigations of these genes are generally scarce, we provided functional evidence that independent loss of TRIM17 in NMRs and BMRs might be beneficial for neuronal survival under hypoxia, supporting the positive role of eliminating TRIM17 function in hypoxia adaptation. Our results also suggested that pseudogenes, together with positively selected genes, reinforced subterranean adaptations cooperatively. Conclusions Our study provides new insights into the molecular underpinnings of subterranean adaptations and highlights the importance of gene losses in mammalian evolution. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-022-01243-0.
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Affiliation(s)
- Zhizhong Zheng
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China
| | - Rong Hua
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China.,Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Guoqiang Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.,Joint Laboratory of Animal Models for Human Diseases and Drug Development, Soochow University and Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Hui Yang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, China.
| | - Peng Shi
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, China. .,Joint Laboratory of Animal Models for Human Diseases and Drug Development, Soochow University and Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China. .,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China. .,School of Future Technology, University of Chinese Academy of Sciences, Beijing, 101408, China.
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Defeudis G, Mazzilli R, Tenuta M, Rossini G, Zamponi V, Olana S, Faggiano A, Pozzilli P, Isidori AM, Gianfrilli D. Erectile dysfunction and diabetes: A melting pot of circumstances and treatments. Diabetes Metab Res Rev 2022; 38:e3494. [PMID: 34514697 PMCID: PMC9286480 DOI: 10.1002/dmrr.3494] [Citation(s) in RCA: 122] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus (DM), a chronic metabolic disease characterised by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM have been increasing over the years. The complications of DM represent a serious health problem. The long-term complications include macroangiopathy, microangiopathy and neuropathy as well as sexual dysfunction (SD) in both men and women. Erectile dysfunction (ED) has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5-fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity and increased caloric consumption. Although lifestyle changes may help improve sexual function, specific treatments are often needed. This study aims to review the definition and prevalence of ED in DM, the impact of DM complications and DM treatment on ED and, finally, the current and emerging therapies for ED in patients with DM.
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Affiliation(s)
- Giuseppe Defeudis
- Unit of Endocrinology and DiabetesDepartment of MedicineUniversity Campus Bio‐Medico di RomaRomeItaly
| | - Rossella Mazzilli
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Marta Tenuta
- Department of Experimental MedicineSapienza University of RomeRomeItaly
| | - Giovanni Rossini
- Unit of Endocrinology and DiabetesDepartment of MedicineUniversity Campus Bio‐Medico di RomaRomeItaly
| | - Virginia Zamponi
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Soraya Olana
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Antongiulio Faggiano
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | - Paolo Pozzilli
- Unit of Endocrinology and DiabetesDepartment of MedicineUniversity Campus Bio‐Medico di RomaRomeItaly
| | - Andrea M. Isidori
- Department of Experimental MedicineSapienza University of RomeRomeItaly
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Zhao X, Liu S, Wang X, Chen Y, Pang P, Yang Q, Lin J, Deng S, Wu S, Fan G, Wang B. Diabetic cardiomyopathy: Clinical phenotype and practice. Front Endocrinol (Lausanne) 2022; 13:1032268. [PMID: 36568097 PMCID: PMC9767955 DOI: 10.3389/fendo.2022.1032268] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is a pathophysiological condition of cardiac structure and function changes in diabetic patients without coronary artery disease, hypertension, and other types of heart diseases. DCM is not uncommon in people with diabetes, which increases the risk of heart failure. However, the treatment is scarce, and the prognosis is poor. Since 1972, one clinical study after another on DCM has been conducted. However, the complex phenotype of DCM still has not been fully revealed. This dilemma hinders the pace of understanding the essence of DCM and makes it difficult to carry out penetrating clinical or basic research. This review summarizes the literature on DCM over the last 40 years and discusses the overall perspective of DCM, phase of progression, potential clinical indicators, diagnostic and screening criteria, and related randomized controlled trials to understand DCM better.
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Affiliation(s)
- Xudong Zhao
- Department of Endocrine and Metabolic Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Shengwang Liu
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Xiao Wang
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Yibing Chen
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Pai Pang
- Department of Endocrine and Metabolic Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Qianjing Yang
- Department of Endocrine and Metabolic Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Jingyi Lin
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Shuaishuai Deng
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Shentao Wu
- Department of Endocrine and Metabolic Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Guanwei Fan
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
| | - Bin Wang
- Department of Endocrine and Metabolic Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Xiqing, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Xiqing, Tianjin, China
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Freitas GN, Silva CDO. Cardioprotector effect of Phosphodiesterase 5 inhibitors in experimental model for Diabetes Mellitus. ABCS HEALTH SCIENCES 2021. [DOI: 10.7322/abcshs.2019164.1433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Diabetes mellitus (DM) is considered a 21st century pandemic and is often associated with cardiovascular disease (CVD). The aim of this integrative review was to analyze the cardioprotective effects of phosdodiesterase-5 (PDE5i) inhibitors in experimental diabetes models. The articles were selected from the PubMed, SciElo and LILACS databases from 2014 to 2019. The following descriptors were used in combination with the Boolean operators: Diabetes mellitus experimental AND Phosphodiesterase 5 inhibitors; Diabetic cardiomyopathies AND Phosphodiesterase 5 inhibitors. An initial sample of 155 articles was obtained, of which six met the criteria for the synthesis of the review. The studies analyzed showed that treatment with PDE5i in experimental models, resulted in positive effects on cardiac function and metabolic parameters. Similar results have also been seen in humans. The reduction in cardiac hypertrophy, apoptosis of cardiomyocytes, pro-inflammatory factors and oxidative stress and the modulation of transcription factors involved in diabetes homeostasis, were prevalent among studies. The mechanisms of action involved in cardioprotection have not yet been fully elucidated, however the restoration of the activated cyclic guanosine monofate (cGMP) pathway by soluble guanylate cyclase (sGC) via nitric oxide (NO) was a common mechanism among the studies.
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40
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Stanton AM, Vaduganathan M, Chang LS, Turchin A, Januzzi JL, Aroda VR. Asymptomatic Diabetic Cardiomyopathy: an Underrecognized Entity in Type 2 Diabetes. Curr Diab Rep 2021; 21:41. [PMID: 34580767 DOI: 10.1007/s11892-021-01407-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/12/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF), with diabetic cardiomyopathy (DbCM) referring to abnormal heart structure in the absence of other driving cardiac factors such as hypertension, coronary artery disease (CAD), and valvular heart disease. Stage B DbCM is commonly asymptomatic and represents a form of stage B HF; DbCM thus represents a transitional phenotype prior to onset of symptomatic HF. The pathogenesis of DbCM is not fully elucidated but involves hyperglycemia, insulin resistance, increased free fatty acids (FFA), lipotoxicity, oxidative stress, advanced glycation end product (AGE) formation, activation of the renin-angiotensin-aldosterone system (RAAS) with an increase in angiotensin II, and dyshomeostasis of calcium, which all contribute to left ventricular hypertrophy (LVH) and cardiac systolic and diastolic dysfunction. Although DbCM is an established pathogenic process, it is underrecognized clinically due to its commonly asymptomatic nature. Raising awareness to identify high-risk individuals with stage B HF due to DbCM, who may subsequently progress to overt HF (stage C/D HF), as well as identifying new pharmacological agents and approaches to prevent functional decline, may help reduce this global health problem. The aim of this review is to focus on stage B DbCM; provide data on diagnostic approaches, current therapies, and potential therapies under investigation; and highlight the need to raise awareness and interdisciplinary dialogue among clinicians and researchers. RECENT FINDINGS There are no currently approved therapeutic strategies to treat or prevent progression of stage B DbCM, but multiple attempts are being made to target different pathogenic mechanisms involved in the development of DbCM. Recent cardiovascular (CV) outcome trials (CVOTs) have identified newer therapeutic agents with CV benefit, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors that reduce hospitalization for HF and glucagon-like peptide-1 (GLP-1) receptor agonists that reduce major adverse CV events (MACE), though without consistent effect on HF outcomes. Recent clinical practice guidelines recommend screening patients at high risk for HF. Further definition and interdisciplinary discussion of high-yield populations to screen, appropriate subsequent evaluation and intervention are needed to advance this area. DbCM is a complex entity that results from multiple pathogenic mechanisms triggered by impairment of glucose and lipid metabolism over many years. DbCM is commonly asymptomatic and represents a form of stage B HF. It is an underrecognized process that may progress to functional decline and overt HF. Although newer medications approved for the treatment of T2D may play an important role in reducing the risk of HF complications, less focus has been placed on earlier recognition and treatment of DbCM while asymptomatic. Additional efforts should be made to further study and target this stage in order to decrease the overall burden of HF.
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Affiliation(s)
- Ana Maria Stanton
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Ave, Office 381, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Muthiah Vaduganathan
- Harvard Medical School, Boston, MA, USA
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Lee-Shing Chang
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Ave, Office 381, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Alexander Turchin
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Ave, Office 381, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - James L Januzzi
- Harvard Medical School, Boston, MA, USA
- Cardiology Division, Massachusetts General Hospital, Baim Institute for Clinical Research, Boston, MA, USA
| | - Vanita R Aroda
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Ave, Office 381, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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Campolo F, Pofi R, Venneri MA, Isidori AM. Priming metabolism with the type 5 phosphodiesterase: the role of cGMP-hydrolyzing enzymes. Curr Opin Pharmacol 2021; 60:298-305. [PMID: 34507030 DOI: 10.1016/j.coph.2021.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/24/2021] [Accepted: 08/09/2021] [Indexed: 12/18/2022]
Abstract
The cyclic guanosine monophosphate (cGMP) signaling system is one of the most prominent regulators of many physiopathological processes in humans and rodents. It has been strongly established as an accomplished cellular signal involved in the regulation of energy homeostasis and cell metabolism, and pharmacological enhancement of cGMP has shown beneficial effects in metabolic disorders models. cGMP intracellular levels are finely regulated by phosphodiesterases (PDEs). The main enzyme responsible for the degradation of cGMP is PDE5. Preclinical and clinical studies have shown that PDE5 inhibitors (PDE5i) have beneficial effects on improving insulin resistance and glucose metabolism representing a promising therapeutic strategy for the treatment of metabolic disorders. This review aims to describe the molecular basis underlying the use of PDE5i to prompt cell metabolism and summarize current clinical trials assessing the effects of PDE5i on glucose metabolism.
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Affiliation(s)
- Federica Campolo
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Riccardo Pofi
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Mary Anna Venneri
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Italy.
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Shirvaliloo M. Targeting the SARS-CoV-2 3CL pro and NO/cGMP/PDE5 pathway in COVID-19: a commentary on PDE5 inhibitors. Future Cardiol 2021; 17:765-768. [PMID: 33576273 PMCID: PMC7885524 DOI: 10.2217/fca-2020-0201] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/15/2021] [Indexed: 01/03/2023] Open
Affiliation(s)
- Milad Shirvaliloo
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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Cardiac Fibrosis and Fibroblasts. Cells 2021; 10:cells10071716. [PMID: 34359886 PMCID: PMC8306806 DOI: 10.3390/cells10071716] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/05/2021] [Accepted: 07/05/2021] [Indexed: 12/24/2022] Open
Abstract
Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are differentiated primarily from resident fibroblasts. Collagen can compensate for the dead cells produced by injury. The appropriate production of collagen is beneficial for preserving the structural integrity of the heart, and protects the heart from cardiac rupture. However, excessive deposition of collagen causes cardiac dysfunction. Recent studies have demonstrated that myofibroblasts can change their phenotypes. In addition, myofibroblasts are found to have functions other than ECM production. Myofibroblasts have macrophage-like functions, in which they engulf dead cells and secrete anti-inflammatory cytokines. Research into fibroblasts has been delayed due to the lack of selective markers for the identification of fibroblasts. In recent years, it has become possible to genetically label fibroblasts and perform sequencing at single-cell levels. Based on new technologies, the origins of fibroblasts and myofibroblasts, time-dependent changes in fibroblast states after injury, and fibroblast heterogeneity have been demonstrated. In this paper, recent advances in fibroblast and myofibroblast research are reviewed.
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Zhang X, Hu C, Yuan XP, Yuan YP, Song P, Kong CY, Teng T, Hu M, Xu SC, Ma ZG, Tang QZ. Osteocrin, a novel myokine, prevents diabetic cardiomyopathy via restoring proteasomal activity. Cell Death Dis 2021; 12:624. [PMID: 34135313 PMCID: PMC8209005 DOI: 10.1038/s41419-021-03922-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 02/06/2023]
Abstract
Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.
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Affiliation(s)
- Xin Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Can Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Xiao-Pin Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Yu-Pei Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Peng Song
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Chun-Yan Kong
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Teng Teng
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Min Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Si-Chi Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China.
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China.
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Liu M, López de Juan Abad B, Cheng K. Cardiac fibrosis: Myofibroblast-mediated pathological regulation and drug delivery strategies. Adv Drug Deliv Rev 2021; 173:504-519. [PMID: 33831476 PMCID: PMC8299409 DOI: 10.1016/j.addr.2021.03.021] [Citation(s) in RCA: 173] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/16/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023]
Abstract
Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into myofibroblasts (myoFbs) that are major mediator cells in the pathological remodeling. MyoFbs exhibit proliferative and secretive characteristics, and contribute to extracellular matrix (ECM) turnover, collagen deposition. The persistent functions of myoFbs lead to fibrotic scars and cardiac dysfunction. The anti-fibrotic treatment is hindered by the elusive mechanism of fibrosis and lack of specific targets on myoFbs. In this review, we will outline the progress of cardiac fibrosis and its contributions to the heart failure. We will also shed light on the role of myoFbs in the regulation of adverse remodeling. The communication between myoFbs and other cells that are involved in the heart injury and repair respectively will be reviewed in detail. Then, recently developed therapeutic strategies to treat fibrosis will be summarized such as i) chimeric antigen receptor T cell (CAR-T) therapy with an optimal target on myoFbs, ii) direct reprogramming from stem cells to quiescent CFs, iii) "off-target" small molecular drugs. The application of nano/micro technology will be discussed as well, which is involved in the construction of cell-based biomimic platforms and "pleiotropic" drug delivery systems.
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Affiliation(s)
- Mengrui Liu
- Department of Molecular Biomedical Sciences, North Carolina State University, NC, USA; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, USA
| | - Blanca López de Juan Abad
- Department of Molecular Biomedical Sciences, North Carolina State University, NC, USA; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences, North Carolina State University, NC, USA; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, USA.
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Chen S, Yan C. An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases. Expert Opin Drug Discov 2021; 16:183-196. [PMID: 32957823 PMCID: PMC7854486 DOI: 10.1080/17460441.2020.1821643] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Cyclic nucleotides, cAMP, and cGMP, are important second messengers of intracellular signaling and play crucial roles in cardiovascular biology and diseases. Cyclic nucleotide phosphodiesterases (PDEs) control the duration, magnitude, and compartmentalization of cyclic nucleotide signaling by catalyzing the hydrolysis of cyclic nucleotides. Individual PDEs modulate distinct signaling pathways and biological functions in the cell, making it a potential therapeutic target for the treatment of different cardiovascular disorders. The clinical success of several PDE inhibitors has ignited continued interest in PDE inhibitors and in PDE-target therapeutic strategies. AREAS COVERED This review concentrates on recent research advances of different PDE isoforms with regard to their expression patterns and biological functions in the heart. The limitations of current research and future directions are then discussed. The current and future development of PDE inhibitors is also covered. EXPERT OPINION Despite the therapeutic success of several marketed PDE inhibitors, the use of PDE inhibitors can be limited by their side effects, lack of efficacy, and lack of isoform selectivity. Advances in our understanding of the mechanisms by which cellular functions are changed through PDEs may enable the development of new approaches to achieve effective and specific PDE inhibition for various cardiac therapies.
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Affiliation(s)
- Si Chen
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
- Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Chen Yan
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
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Pofi R, Giannetta E, Galea N, Francone M, Campolo F, Barbagallo F, Gianfrilli D, Venneri MA, Filardi T, Cristini C, Antonini G, Badagliacca R, Frati G, Lenzi A, Carbone I, Isidori AM. Diabetic Cardiomiopathy Progression is Triggered by miR122-5p and Involves Extracellular Matrix: A 5-Year Prospective Study. JACC Cardiovasc Imaging 2020; 14:1130-1142. [PMID: 33221242 DOI: 10.1016/j.jcmg.2020.10.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The purpose of this study was to follow the long-term progression of diabetic cardiomyopathy by combining cardiac magnetic resonance (CMR) and molecular analysis. BACKGROUND The evolution of diabetic cardiomyopathy to heart failure affects patients'morbidity and mortality. CMR is the gold standard to assess cardiac remodeling, but there is a lack of markers linked to the mechanism of diabetic cardiomyopathy progression. METHODS Five-year longitudinal study on patients with type 2 diabetes mellitus (T2DM) enrolled in the CECSID (Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes) trial compared with nondiabetic age-matched controls. CMR with tagging together with metabolic and molecular assessments were performed at baseline and 5-year follow-up. RESULTS A total of 79 men (age 64 ± 8 years) enrolled, comprising 59 men with T2DM compared with 20 nondiabetic age-matched controls. Longitudinal CMR with tagging showed an increase in ventricular mass (ΔLVMi = 13.47 ± 29.66 g/m2; p = 0.014) and a borderline increase in end-diastolic volume (ΔEDVi = 5.16 ± 14.71 ml/m2; p = 0.056) in men with T2DM. Cardiac strain worsened (Δσ = 1.52 ± 3.85%; p = 0.033) whereas torsion was unchanged (Δθ = 0.24 ± 4.04°; p = 0.737), revealing a loss of the adaptive equilibrium between strain and torsion. Contraction dynamics showed a decrease in the systolic time-to-peak (ΔTtP = -35.18 ± 28.81 ms; p < 0.001) and diastolic early recoil-rate (ΔRR = -20.01 ± 19.07 s-1; p < 0.001). The ejection fraction and metabolic parameters were unchanged. Circulating miR microarray revealed an up-regulation of miR122-5p. Network analysis predicted the matrix metalloproteinases (MMPs) MMP-16 and MMP-2 and their regulator (tissue inhibitors of metalloproteinases) as targets. In db/db mice we demonstrated that miR122-5p expression is associated with diabetic cardiomyopathy, that in the diabetic heart is overexpressed, and that, in vitro, it regulates MMP-2. Finally, we demonstrated that miR122-5p overexpression affects the extracellular matrix through MMP-2 modulation. CONCLUSIONS Within 5 years of diabetic cardiomyopathy onset, increasing cardiac hypertrophy is associated with progressive impairment in strain, depletion of the compensatory role of torsion, and changes in viscoelastic contraction dynamics. These changes are independent of glycemic control and paralleled by the up-regulation of specific microRNAs targeting the extracellular matrix. (Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes [CECSID]; NCT00692237).
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Affiliation(s)
- Riccardo Pofi
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Nicola Galea
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Marco Francone
- Department of Radiological, Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Federica Campolo
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Federica Barbagallo
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Daniele Gianfrilli
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Mary Anna Venneri
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Tiziana Filardi
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Cristiano Cristini
- Department of Obstetrical and Gynaecological Sciences and Urological Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Gabriele Antonini
- Department of Obstetrical and Gynaecological Sciences and Urological Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Roberto Badagliacca
- Department of Cardiovascular and Respiratory Diseases, "Sapienza" University of Rome, Rome, Italy
| | - Giacomo Frati
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) NEUROMED, Pozzilli, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Iacopo Carbone
- Department of Radiological, Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
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Barbagallo F, Campolo F, Franceschini E, Crecca E, Pofi R, Isidori AM, Venneri MA. PDE5 Inhibitors in Type 2 Diabetes Cardiovascular Complications. ENDOCRINES 2020; 1:90-101. [DOI: 10.3390/endocrines1020009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023] Open
Abstract
Pharmacological inhibition of Phosphodiesterase type 5 (PDE5) proved its efficacy treating several pathological conditions, such as erectile dysfunction and pulmonary hypertension. Nowadays, its benefits on cardiovascular diseases are well documented, particularly in the treatment of type 2 diabetes (T2DM)-related cardiovascular complications. In this context, treatment of T2DM with PDE5 inhibitors, such as sildenafil, tadalafil or vardenafil ameliorates endothelial dysfunction both in patients and animal models through an augmented flow mediated dilation rate and an up-regulation of endothelial markers; it also reduces the inflammatory state by down-regulating inflammatory cytokines expression and improves diabetic cardiomyopathy and ischemia-reperfusion injury mainly through the activation of NO-cGMP-PKG pathway. The present review summarizes the state of art on PDE5 inhibition in the treatment of cardiovascular complications in T2DM.
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Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol 2020; 17:585-607. [PMID: 32080423 PMCID: PMC7849055 DOI: 10.1038/s41569-020-0339-2] [Citation(s) in RCA: 474] [Impact Index Per Article: 94.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2020] [Indexed: 02/07/2023]
Abstract
The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.
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Affiliation(s)
- Yi Tan
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.
- Wendy Novak Diabetes Center, University of Louisville, Norton Children's Hospital, Louisville, KY, USA.
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
| | - Zhiguo Zhang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, China
| | - Chao Zheng
- The Second Affiliated Hospital Center of Chinese-American Research Institute for Diabetic Complications, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kupper A Wintergerst
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
- Wendy Novak Diabetes Center, University of Louisville, Norton Children's Hospital, Louisville, KY, USA
- Division of Endocrinology, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
| | - Bradley B Keller
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
- Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY, USA
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.
- Wendy Novak Diabetes Center, University of Louisville, Norton Children's Hospital, Louisville, KY, USA.
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
- Department of Radiation Oncology, University of Louisville School of Medicine, Louisville, KY, USA.
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50
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Isidori AM, Giannetta E, Pofi R, Venneri MA, Gianfrilli D, Campolo F, Mastroianni CM, Lenzi A, d'Ettorre G. Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project. Andrology 2020; 9:33-38. [PMID: 32526061 PMCID: PMC7307129 DOI: 10.1111/andr.12837] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 01/08/2023]
Abstract
Background A pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, “cytokines storm,” that causes the systemic complications of COVID‐19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Objectives Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway in modulating low‐grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti‐inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID‐19 disease. Materials and methods We performed a systematic review of all evidence documenting any involvement of the NO‐cGMP‐PDE5 axis in the pathophysiology of COVID‐19, presenting the ongoing clinical trials aimed at modulating this axis, including our own “silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID‐19 (DEDALO trial).” Results The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID‐19 by (i) counteracting the Ang‐II‐mediated downregulation of AT‐1 receptor; (ii) acting on monocyte switching, thus reducing pro‐inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage‐necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. Discussion and Conclusion If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID‐19 in developing countries.
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Affiliation(s)
- Andrea M Isidori
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Riccardo Pofi
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Mary A Venneri
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Daniele Gianfrilli
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Federica Campolo
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Claudio M Mastroianni
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Policlinico Umberto I of Rome, Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Sapienza" University of Rome, Rome, Italy
| | - Gabriella d'Ettorre
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Policlinico Umberto I of Rome, Rome, Italy
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