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Marunouchi T, Kyono M, Kikuchi N, Tanonaka K. Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY PLUS 2025; 12:100292. [PMID: 40134584 PMCID: PMC11932663 DOI: 10.1016/j.jmccpl.2025.100292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/07/2025] [Accepted: 03/08/2025] [Indexed: 03/27/2025]
Abstract
The size of the infarct area following acute myocardial infarction (AMI) is a critical prognostic factor. Caspase-11-dependent pyroptosis has been implicated as a key mechanism driving cardiomyocyte death after AMI. However, no therapeutic agents have been developed to inhibit myocardial cell death by targeting caspase-11. This study investigates the effects of gemfibrozil, a potential caspase-11 inhibitor, on ischemia/reperfusion-induced myocardial pyroptosis in mice. To model AMI, the left coronary artery of C57BL/6 N mice was ligated for 1 h, followed by reperfusion. Levels of cleaved caspase-11 and the N-terminal fragment of gasdermin D (GSDMD-N) in ischemic myocardial tissue increased progressively over time after ischemia/reperfusion. Gemfibrozil treatment during reperfusion significantly attenuated these increases in cleaved caspase-11 and GSDMD-N levels. Moreover, gemfibrozil reduced the extent of myocardial infarct size during reperfusion. In cultured cardiomyocytes isolated from adult mice, hypoxia/reoxygenation-induced increases in caspase-11 and GSDMD cleavage were similarly mitigated by gemfibrozil, which concurrently prevented necrotic cell death. These findings demonstrate the involvement of caspase-11-dependent pyroptosis in myocardial cell death following ischemia/reperfusion and suggest that gemfibrozil holds promise as a therapeutic agent for reducing myocardial infarct size after AMI.
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Affiliation(s)
- Tetsuro Marunouchi
- Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Japan
| | - Mayu Kyono
- Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Japan
| | - Naoko Kikuchi
- Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Japan
| | - Kouichi Tanonaka
- Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Japan
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2
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Singh A, Chaudhary R. Potentials of peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ: An in-depth and comprehensive review of their molecular mechanisms, cellular Signalling, immune responses and therapeutic implications in multiple diseases. Int Immunopharmacol 2025; 155:114616. [PMID: 40222274 DOI: 10.1016/j.intimp.2025.114616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/21/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors, have emerged as a key regulator of various biological processes, underscoring their relevance in the pathophysiology and treatment of numerous diseases. PPARs are primarily recognized for their critical role in lipid and glucose metabolism, which underpins their therapeutic applications in managing type 2 diabetes mellitus. Beyond metabolic disorders, they have gained attention for their involvement in immune modulation, making them potential targets for autoimmune-related inflammatory diseases. Furthermore, PPAR's ability to regulate proliferation, differentiation, and apoptosis has positioned them as promising candidates in oncology. Their anti-inflammatory and anti-fibrotic properties further highlight their potential in dermatological and cardiovascular conditions, where dysregulated inflammatory responses contribute to disease progression. Recent advancements have elucidated the molecular mechanisms of different PPAR isoforms, including their regulation of key signalling pathways such as NF-κB and MAPK, which are crucial in inflammation and cellular stress responses. Additionally, their interactions with co-factors and post-translational modifications further diversify their functional roles. The therapeutic potential of various PPAR agonists has been extensively explored, although challenges related to side effects and target specificity remain. This growing body of evidence underscores the significance of PPARs in understanding the molecular basis of diseases and advancing therapeutic interventions, paving way for targeted treatment approach across a wide spectrum of medical conditions. Here, we provide a comprehensive and detailed perspective of PPARs and their potential across different health conditions to advance our understanding, elucidate underlying mechanisms, and facilitate the development of potential treatment strategies.
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Affiliation(s)
- Alpana Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India.
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3
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Li H, Ouyang Y, Lv H, Liang H, Luo S, Zhang Y, Mao H, Chen T, Chen W, Zhou Y, Liu Q. Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells. Biomaterials 2025; 315:122926. [PMID: 39500111 DOI: 10.1016/j.biomaterials.2024.122926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 09/05/2024] [Accepted: 10/27/2024] [Indexed: 12/09/2024]
Abstract
Klotho is an anti-aging protein produced primarily by tubular epithelial cells (TECs). Down-regulated expression of Klotho in injured TECs plays a key pathogenic role in promoting acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet therapeutic approaches targeting the restoration of renal Klotho levels remain challenging for clinical application. Here, we synthesize polydopamine-polyethylenimine-l-serine-Klotho plasmid nanoparticles (PPSK NPs), which can safely and selectively deliver the Klotho gene to the injured TECs through binding kidney injury molecule-1 and maintain the expression of Klotho protein. In vitro, PPSK NPs effectively reduce the hypoxia-reoxygenation-induced reactive oxygen species production and fibrotic gene expression. In the unilateral ischemia-reperfusion injury- and folic acid-induced AKI-CKD transition mouse models, a single low-dose injection of PPSK NPs is sufficient to preserve the normal kidney architecture and prevent renal fibrosis. Mechanismly, the protective effect of PPSK NPs relies on upregulating a key molecule peroxisome proliferator-activated receptor alpha (PPARα) via the inhibition of p38 and JNK phosphorylation, which in turn improves tubular fatty acid beta-oxidation and reduces renal lipid accumulation, thereby protecting against kidney fibrosis. In conclusion, our results highlight the translational potential of nanoparticle-based Klotho gene therapy in preventing the AKI-CKD transition.
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Affiliation(s)
- Hongyu Li
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Yuying Ouyang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Haoran Lv
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Hanzhi Liang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Siweier Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yating Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Haiping Mao
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Tianfeng Chen
- Department of Chemistry, Jinan University, Guangzhou, 510632, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China.
| | - Yiming Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Qinghua Liu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China; Department of Nephrology, Jieyang People's Hospital, Jieyang, 522000, China.
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4
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Tashkandi AJ, Gorman A, McGoldrick Mathers E, Carney G, Yacoub A, Setyaningsih WAW, Kuburas R, Margariti A. Metabolic and Mitochondrial Dysregulations in Diabetic Cardiac Complications. Int J Mol Sci 2025; 26:3016. [PMID: 40243689 PMCID: PMC11988959 DOI: 10.3390/ijms26073016] [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: 02/01/2025] [Revised: 03/16/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
The growing prevalence of diabetes highlights the urgent need to study diabetic cardiovascular complications, specifically diabetic cardiomyopathy, which is a diabetes-induced myocardial dysfunction independent of hypertension or coronary artery disease. This review examines the role of mitochondrial dysfunction in promoting diabetic cardiac dysfunction and highlights metabolic mechanisms such as hyperglycaemia-induced oxidative stress. Chronic hyperglycaemia and insulin resistance can activate harmful pathways, including advanced glycation end-products (AGEs), protein kinase C (PKC) and hexosamine signalling, uncontrolled reactive oxygen species (ROS) production and mishandling of Ca2+ transient. These processes lead to cardiomyocyte apoptosis, fibrosis and contractile dysfunction. Moreover, endoplasmic reticulum (ER) stress and dysregulated RNA-binding proteins (RBPs) and extracellular vesicles (EVs) contribute to tissue damage, which drives cardiac function towards heart failure (HF). Advanced patient-derived induced pluripotent stem cell (iPSC) cardiac organoids (iPS-COs) are transformative tools for modelling diabetic cardiomyopathy and capturing human disease's genetic, epigenetic and metabolic hallmarks. iPS-COs may facilitate the precise examination of molecular pathways and therapeutic interventions. Future research directions encourage the integration of advanced models with mechanistic techniques to promote novel therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | - Refik Kuburas
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
| | - Andriana Margariti
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
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5
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Zhang S, Ye Y, Li Q, Zhao J, Song R, Huang C, Lu X, Huang C, Yin L, You Q. Andrographolide Attenuates Myocardial Ischemia-Reperfusion Injury in Mice by Up-Regulating PPAR-α. Inflammation 2024:10.1007/s10753-024-02193-1. [PMID: 39585583 DOI: 10.1007/s10753-024-02193-1] [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: 09/08/2024] [Revised: 11/06/2024] [Accepted: 11/13/2024] [Indexed: 11/26/2024]
Abstract
Andrographolide (AGP), a bioactive diterpene lactone, is an active constituent extracted from Andrographis paniculata. It has many biological activities, such as antioxidant, antitumor, antivirus, anti-inflammation, hepatoprotection, and cardioprotection. The aim of the present study is to investigate the cardioprotective effects of AGP in a mouse model of myocardial ischemia-reperfusion injury (MIRI). Adult male C57BL/6 J mice were pre-treated orally with AGP (25 mg/kg) for six days. After 30 min of the left anterior descending coronary artery occlusion followed by 24 h of reperfusion, mice received an additional dose of AGP. The results showed that: (i) AGP pretreatment significantly reduced myocardial infarct size and cardiac injury biomarkers in MIRI mice and improved left ventricular ejection fraction (EF) and fractional shortening (FS); (ii) AGP pretreatment attenuated MIRI-induced oxidative stress imbalance in MIRI mice by increasing total antioxidant capacity (T-AOC) and reducing the levels of hydrogen peroxide (H2O2), nitric oxide (NO), malondialdehyde (MDA), and dihydroethidium (DHE); (iii) AGP pretreatment increased Bcl-2 expression and decreased caspase-3 and Bax expression in ischemic myocardial tissue, along with a reduction in TUNEL-positive cells. Further analysis showed that stimulation by I/R decreased peroxisome proliferator-activated receptor-α (PPAR-α) expression in ischemic cardiac tissue, which was prevented by AGP administration. Moreover, administration of the PPAR-α antagonist GW6471 (1 mg/kg) abolished the protective effect of AGP on oxidative stress and apoptosis in the ischemic heart tissue of mice stimulated by ischemia-reperfusion. Taken together, these results suggest that AGP attenuates MIRI-induced cardiac injury by up-regulating PPAR-α expression, thereby preventing oxidative stress and cellular apoptosis.
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Affiliation(s)
- Shenjie Zhang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Ying Ye
- Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Qi Li
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Juan Zhao
- Department of Cardiology, Tongzhou People's Hospital, 999 Jianshe Road, Nantong, 226300, Jiangsu Province, China
| | - Rongrong Song
- Department of Emergency and Critical Care Medicine, Tongzhou People's Hospital, 999 Jianshe Road, Nantong, 226300, Jiangsu Province, China
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Xu Lu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Chen Huang
- Department of Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
| | - Le Yin
- Department of Cardiology, Tongzhou People's Hospital, 999 Jianshe Road, Nantong, 226300, Jiangsu Province, China.
| | - Qingsheng You
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
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6
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Oidor-Chan VH, Sánchez-López A, Cano-Martinez A, García-Niño WR, Soria-Castro E, del Valle-Mondragón L, Zarco-Olvera G, Patlán M, Guarner-Lans V, Rodríguez-Maldonado E, Flores-Estrada J, Castrejón-Téllez V, Ibarra-Lara L. Pharmacological Preconditioning with Fenofibrate in Cardiomyocyte Cultures of Neonatal Rats Subjected to Hypoxia/Reoxygenation, High Glucose, and Their Combination. Int J Mol Sci 2024; 25:11391. [PMID: 39518943 PMCID: PMC11547148 DOI: 10.3390/ijms252111391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/15/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024] Open
Abstract
Pharmacological preconditioning is an alternative to protect the heart against the consequences of damage from ischemia/reperfusion (I/R). It is based on the administration of specific drugs that imitate the effect of ischemic preconditioning (IPC). Peroxisomal proliferator-activated receptors (PPARs) can prevent apoptosis in pathologies such as I/R and heart failure. Therefore, our objective was to determine if the stimulation of PPARα with fenofibrate (feno) decreases the apoptotic process induced by hypoxia/reoxygenation (HR), high glucose (HG), and HR/HG. For that purpose, cardiomyocyte cultures were divided into the following groups: Group 1-control (Ctrl); Group 2-HR; Group 3-HR + 10 μM feno; Group 4-HG, (25 mM glucose); Group 5-HG + feno; Group 6-HR/HG, and Group 7-HR/HG + feno. Our results indicate that cell viability decreases in neonatal cardiomyocytes undergoing HR, HG, and their combination, while feno improved cell viability. Feno treatment decreased apoptosis compared with HG-, HR-, or HG/HR-vehicle-treated. Nuclear- and mitochondrial-apoptosis markers increased in neonatal cardiomyocytes from HR, HG, and HR/HG; while the cytotoxicity decreased in cells treated with feno. In addition, the expression of Bax, Bad, and caspase 9 decreased due to feno, while 14-3-3ɛ and Bcl2 were increased. Inner mitochondrial cytochrome C increased with feno in every condition, as well as mitochondrial activity. Feno treatment prevented injury in the ultrastructure and in the mitochondrial membranes. Thus, our results suggest that feno decreases apoptosis in neonatal cardiomyocytes, improving the ultrastructure of mitochondria in the pathological conditions studied.
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Affiliation(s)
- Víctor Hugo Oidor-Chan
- Department of Biotechnology, Autonomous Metropolitan University, Iztapalapa Campus, Av. Ferrocarril de San Rafael Atlixco 186, Col. Leyes de Reforma 1ª. Sección, Alcaldía Iztapalapa, Mexico City 09310, Mexico;
| | - Araceli Sánchez-López
- Department of Pharmacobiology, Center for Research and Advanced Studies of the National Polytechnic Institute, Calz. de los Tenorios 235, Col Granjas Coapa, Tlalpan, Mexico City 14330, Mexico;
| | - Agustina Cano-Martinez
- Department of Physiology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (A.C.-M.); (V.G.-L.)
| | - Willy Ramses García-Niño
- Department of Cardiovascular Biomedicine, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (W.R.G.-N.); (E.S.-C.)
| | - Elizabeth Soria-Castro
- Department of Cardiovascular Biomedicine, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (W.R.G.-N.); (E.S.-C.)
| | - Leonardo del Valle-Mondragón
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (L.d.V.-M.); (G.Z.-O.)
| | - Gabriela Zarco-Olvera
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (L.d.V.-M.); (G.Z.-O.)
| | - Mariana Patlán
- Subdirection of Basic and Technological Research, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico;
| | - Veronica Guarner-Lans
- Department of Physiology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (A.C.-M.); (V.G.-L.)
| | - Emma Rodríguez-Maldonado
- Laboratory of Cell Biology, Department of Physiology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico;
| | - Javier Flores-Estrada
- Division of Investigation, Juarez Hospital of Mexico, Av. Instituto Politecnico Nacional No. 5160, Magdalena de las Salinas, Gustavo A. Madero, Mexico City 07760, Mexico;
| | - Vicente Castrejón-Téllez
- Department of Physiology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (A.C.-M.); (V.G.-L.)
| | - Luz Ibarra-Lara
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico; (L.d.V.-M.); (G.Z.-O.)
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7
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Rubio-Tomás T, Soler-Botija C, Martínez-Estrada O, Villena JA. Transcriptional control of cardiac energy metabolism in health and disease: Lessons from animal models. Biochem Pharmacol 2024; 224:116185. [PMID: 38561091 DOI: 10.1016/j.bcp.2024.116185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/27/2024] [Accepted: 03/29/2024] [Indexed: 04/04/2024]
Abstract
Cardiac ATP production is tightly regulated in order to satisfy the evolving energetic requirements imposed by different cues during health and pathological conditions. In order to sustain high ATP production rates, cardiac cells are endowed with a vast mitochondrial network that is essentially acquired during the perinatal period. Nevertheless, adult cardiac cells also adapt their mitochondrial mass and oxidative function to changes in energy demand and substrate availability by fine-tuning the pathways and mitochondrial machinery involved in energy production. The reliance of cardiac cells on mitochondrial metabolism makes them particularly sensitive to alterations in proper mitochondrial function, so that deficiency in energy production underlies or precipitates the development of heart diseases. Mitochondrial biogenesis is a complex process fundamentally controlled at the transcriptional level by a network of transcription factors and co-regulators, sometimes with partially redundant functions, that ensure adequate energy supply to the working heart. Novel uncovered regulators, such as RIP140, PERM1, MED1 or BRD4 have been recently shown to modulate or facilitate the transcriptional activity of the PGC-1s/ERRs/PPARs regulatory axis, allowing cardiomyocytes to adapt to a variety of physiological or pathological situations requiring different energy provision. In this review, we summarize the current knowledge on the mechanisms that regulate cardiac mitochondrial biogenesis, highlighting the recent discoveries of new transcriptional regulators and describing the experimental models that have provided solid evidence of the relevant contribution of these factors to cardiac function in health and disease.
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Affiliation(s)
- Teresa Rubio-Tomás
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion GR-70013, Crete, Greece
| | - Carolina Soler-Botija
- ICREC (Heart Failure and Cardiac Regeneration) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain; CIBER on Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Josep A Villena
- Laboratory of Metabolism and Obesity, Vall d'Hebron-Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; CIBER on Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain.
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8
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Lee S. Cardiovascular Disease and miRNAs: Possible Oxidative Stress-Regulating Roles of miRNAs. Antioxidants (Basel) 2024; 13:656. [PMID: 38929095 PMCID: PMC11200533 DOI: 10.3390/antiox13060656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/28/2024] Open
Abstract
MicroRNAs (miRNAs) have been highlighted as key players in numerous diseases, and accumulating evidence indicates that pathological expressions of miRNAs contribute to both the development and progression of cardiovascular diseases (CVD), as well. Another important factor affecting the development and progression of CVD is reactive oxygen species (ROS), as well as the oxidative stress they may impose on the cells. Considering miRNAs are involved in virtually every biological process, it is not unreasonable to assume that miRNAs also play critical roles in the regulation of oxidative stress. This narrative review aims to provide mechanistic insights on possible oxidative stress-regulating roles of miRNAs in cardiovascular diseases based on differentially expressed miRNAs reported in various cardiovascular diseases and their empirically validated targets that have been implicated in the regulation of oxidative stress.
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Affiliation(s)
- Seahyoung Lee
- Department of Convergence Science, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Republic of Korea
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9
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Liss KHH, Mousa M, Bucha S, Lutkewitte A, Allegood J, Cowart LA, Finck BN. Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury. Sci Rep 2024; 14:3584. [PMID: 38351300 PMCID: PMC10864394 DOI: 10.1038/s41598-024-54122-9] [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: 08/07/2023] [Accepted: 02/08/2024] [Indexed: 02/16/2024] Open
Abstract
Liver failure secondary to metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common cause for liver transplantation in many parts of the world. Moreover, the prevalence of MASLD not only increases the demand for liver transplantation, but also limits the supply of suitable donor organs because steatosis predisposes grafts to ischemia-reperfusion injury (IRI). There are currently no pharmacological interventions to limit hepatic IRI because the mechanisms by which steatosis leads to increased injury are unclear. To identify potential novel mediators of IRI, we used liquid chromatography and mass spectrometry to assess temporal changes in the hepatic lipidome in steatotic and non-steatotic livers after warm IRI in mice. Our untargeted analyses revealed distinct differences between the steatotic and non-steatotic response to IRI and highlighted dynamic changes in lipid composition with marked changes in glycerophospholipids. These findings enhance our knowledge of the lipidomic changes that occur following IRI and provide a foundation for future mechanistic studies. A better understanding of the mechanisms underlying such changes will lead to novel therapeutic strategies to combat IRI.
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Affiliation(s)
- Kim H H Liss
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Muhammad Mousa
- Department of Medicine, Division of Nutritional Science and Obesity Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Shria Bucha
- Washington University in St. Louis, St. Louis, MO, USA
| | - Andrew Lutkewitte
- Department of Medicine, Division of Nutritional Science and Obesity Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jeremy Allegood
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - L Ashley Cowart
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Brian N Finck
- Department of Medicine, Division of Nutritional Science and Obesity Medicine, Washington University School of Medicine, St. Louis, MO, USA.
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10
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More SA, Deore RS, Pawar HD, Sharma C, Nakhate KT, Rathod SS, Ojha S, Goyal SN. CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:1683. [PMID: 38338960 PMCID: PMC10855244 DOI: 10.3390/ijms25031683] [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: 12/31/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-β/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.
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Affiliation(s)
- Sagar A. More
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Rucha S. Deore
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Harshal D. Pawar
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Kartik T. Nakhate
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Sumit S. Rathod
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Sameer N. Goyal
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
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11
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Solati Z, Surendran A, Aukema HM, Ravandi A. Impact of Reperfusion on Plasma Oxylipins in ST-Segment Elevation Myocardial Infarction. Metabolites 2023; 14:19. [PMID: 38248822 PMCID: PMC10821107 DOI: 10.3390/metabo14010019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/23/2024] Open
Abstract
ST-segment elevation myocardial infarction (STEMI) occurs as a result of acute occlusion of the coronary artery. Despite successful reperfusion using primary percutaneous coronary intervention (PPCI), a large percentage of myocardial cells die after reperfusion, which is recognized as ischemia/reperfusion injury (I/R). There are rapid changes in plasma lipidome during myocardial reperfusion injury. However, the impact of coronary artery reperfusion on plasma oxylipins is unknown. This study aimed to investigate alterations in the oxylipin profiles of STEMI patients during ischemia and at various reperfusion time points following PPCI. Blood samples were collected from patients presenting with STEMI prior to PPCI (Isch, n = 45) and subsequently 2 h following successful reperfusion by PPCI (R-2 h, n = 42), after 24 h (R-24 h, n = 44), after 48 h (R-48 h, n = 43), and then 30 days post PPCI (R-30 d, n = 29). As controls, blood samples were collected from age- and sex-matched patients with non-obstructive coronary artery disease after diagnostic coronary angiography. High-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) using deuterated standards was used to identify and quantify oxylipins. In patients presenting with STEMI prior to reperfusion (Isch group), the levels of docosahexaenoic acid (DHA)-derived oxylipins were significantly higher when compared with controls. Their levels were also significantly correlated with the peak levels of creatine kinase (CK) and troponin T(TnT) before reperfusion (CK: r = 0.33, p = 0.046, TnT: r = 0.50, p = 1.00 × 10-3). The total concentrations of oxylipins directly produced by 5-lipoxygenase (5-LOX) were also significantly elevated in the Isch group compared with controls. The ratio of epoxides (generated through epoxygenase) to diols (generated by soluble epoxide hydrolysis (sEH)) was significantly lower in the Isch group compared with the controls. Following reperfusion, there was an overall reduction in plasma oxylipins in STEMI patients starting at 24 h post PPCI until 30 days. Univariate receiver operating characteristic (ROC) curve analysis also showed that an elevated ratio of epoxides to diols during ischemia is a predictor of smaller infarct size in patients with STEMI. This study revealed a large alteration in plasma oxylipins in patients presenting with STEMI when compared with controls. Total oxylipin levels rapidly reduced post reperfusion with stable levels reached 24 h post reperfusion and maintained for up to 30 days post infarct. Given the shifts in plasma oxylipins following coronary artery reperfusion, further research is needed to delineate their clinical impact in STEMI patients.
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Affiliation(s)
- Zahra Solati
- Precision Cardiovascular Medicine Group, St. Boniface Hospital, Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada (H.M.A.)
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
| | - Arun Surendran
- Precision Cardiovascular Medicine Group, St. Boniface Hospital, Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada (H.M.A.)
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
| | - Harold M. Aukema
- Precision Cardiovascular Medicine Group, St. Boniface Hospital, Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada (H.M.A.)
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Amir Ravandi
- Precision Cardiovascular Medicine Group, St. Boniface Hospital, Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada (H.M.A.)
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
- Section of Cardiology, University of Manitoba, Winnipeg, MB R3T 5V6, Canada
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12
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Xia B, Li Q, Zheng K, Wu J, Huang C, Liu K, You Q, Yuan X. Down-regulation of Hrd1 protects against myocardial ischemia-reperfusion injury by regulating PPARα to prevent oxidative stress, endoplasmic reticulum stress, and cellular apoptosis. Eur J Pharmacol 2023; 954:175864. [PMID: 37392829 DOI: 10.1016/j.ejphar.2023.175864] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/07/2023] [Accepted: 06/15/2023] [Indexed: 07/03/2023]
Abstract
The E3 ubiquitin ligase HMG-CoA reductase degradation protein 1 (Hrd1) is a key enzyme for ER-associated degradation of misfolded proteins. Its role in ischemic heart disease has not been fully elucidated. Here, we investigated its effect on oxidative status and cell survival in cardiac ischemia-reperfusion injury (MIRI). We found that virus-induced down-regulation of Hrd1 expression limited infarct size, decreased creatinine kinase (CK) and lactate dehydrogenase (LDH), and preserved cardiac function in mice subjected to left anterior descending coronary artery ligation and reperfusion. Silencing of the Hrd1 gene also prevented the ischemia/reperfusion (I/R)-induced (i) increase in dihydroethidium (DHE) intensity, mitochondrial production of reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO), (ii) decrease in total antioxidant capacity (T-AOC) and glutathione (GSH), (iii) disruption of mitochondrial membrane potential, and (iv) increase in the expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) in ischemic heart tissue. In addition, down-regulation of Hrd1 expression prevented the abnormally increased caspase-3/caspase-9/Bax expression and decreased Bcl-2 expression in ischemic heart tissue of I/R mice. Further analysis showed that the I/R stimulus reduced peroxisome proliferation activated receptor α (PPARα) expression in ischemic heart tissue, which was partially prevented by down-regulation of Hrd1. Pharmacological inhibition of PPARα was able to abolish the preventive effect of down-regulation of Hrd1 on oxidative stress, endoplasmic reticulum stress, and cellular apoptosis in ischemic heart tissue. These data suggest that down-regulation of Hrd1 protects the heart from I/R-induced damage by suppressing oxidative stress and cellular apoptosis likely through PPARα.
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Affiliation(s)
- Boyu Xia
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Qi Li
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Koulong Zheng
- Department of Cardiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jingjing Wu
- Department of Cardiology, Suzhou Kowloon Hospital of Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Kun Liu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Qingsheng You
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
| | - Xiaomei Yuan
- Department of Cardiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
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13
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Tian H, Zhao X, Zhang Y, Xia Z. Abnormalities of glucose and lipid metabolism in myocardial ischemia-reperfusion injury. Biomed Pharmacother 2023; 163:114827. [PMID: 37141734 DOI: 10.1016/j.biopha.2023.114827] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/23/2023] [Accepted: 04/30/2023] [Indexed: 05/06/2023] Open
Abstract
Myocardial ischemia-reperfusion injury is a common condition in cardiovascular diseases, and the mechanism of its occurrence involves multiple complex metabolic pathways and signaling pathways. Among these pathways, glucose metabolism and lipid metabolism play important roles in regulating myocardial energy metabolism. Therefore, this article focuses on the roles of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion injury, including glycolysis, glucose uptake and transport, glycogen metabolism and the pentose phosphate pathway; and triglyceride metabolism, fatty acid uptake and transport, phospholipid metabolism, lipoprotein metabolism, and cholesterol metabolism. Finally, due to the different alterations and development of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion, there are also complex interregulatory relationships between them. In the future, modulating the equilibrium between glucose metabolism and lipid metabolism in cardiomyocytes and ameliorating aberrations in myocardial energy metabolism represent highly promising novel strategies for addressing myocardial ischemia-reperfusion injury. Therefore, a comprehensive exploration of glycolipid metabolism can offer novel theoretical and clinical insights into the prevention and treatment of myocardial ischemia-reperfusion injury.
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Affiliation(s)
- Hao Tian
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Xiaoshuai Zhao
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Yuxi Zhang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Zhongyuan Xia
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
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Sánchez-Aguilar M, Ibarra-Lara L, Cano-Martínez A, Soria-Castro E, Castrejón-Téllez V, Pavón N, Osorio-Yáñez C, Díaz-Díaz E, Rubio-Ruíz ME. PPAR Alpha Activation by Clofibrate Alleviates Ischemia/Reperfusion Injury in Metabolic Syndrome Rats by Decreasing Cardiac Inflammation and Remodeling and by Regulating the Atrial Natriuretic Peptide Compensatory Response. Int J Mol Sci 2023; 24:ijms24065321. [PMID: 36982395 PMCID: PMC10049157 DOI: 10.3390/ijms24065321] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
Metabolic syndrome (MetS) is a cluster of factors that increase the risk of developing diabetes, stroke, and heart failure. The pathophysiology of injury by ischemia/reperfusion (I/R) is highly complex and the inflammatory condition plays an important role by increasing matrix remodeling and cardiac apoptosis. Natriuretic peptides (NPs) are cardiac hormones with numerous beneficial effects mainly mediated by a cell surface receptor named atrial natriuretic peptide receptor (ANPr). Although NPs are powerful clinical markers of cardiac failure, their role in I/R is still controversial. Peroxisome proliferator-activated receptor α agonists exert cardiovascular therapeutic actions; however, their effect on the NPs’ signaling pathway has not been extensively studied. Our study provides important insight into the regulation of both ANP and ANPr in the hearts of MetS rats and their association with the inflammatory conditions caused by damage from I/R. Moreover, we show that pre-treatment with clofibrate was able to decrease the inflammatory response that, in turn, decreases myocardial fibrosis, the expression of metalloprotease 2 and apoptosis. Treatment with clofibrate is also associated with a decrease in ANP and ANPr expression.
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Affiliation(s)
- María Sánchez-Aguilar
- Department of Pharmacology, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (M.S.-A.); (L.I.-L.); (N.P.)
| | - Luz Ibarra-Lara
- Department of Pharmacology, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (M.S.-A.); (L.I.-L.); (N.P.)
| | - Agustina Cano-Martínez
- Department of Physiology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico; (A.C.-M.); (V.C.-T.)
| | - Elizabeth Soria-Castro
- Department of Cardiovascular Biomedicine, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - Vicente Castrejón-Téllez
- Department of Physiology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico; (A.C.-M.); (V.C.-T.)
| | - Natalia Pavón
- Department of Pharmacology, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (M.S.-A.); (L.I.-L.); (N.P.)
| | - Citlalli Osorio-Yáñez
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Apartado Postal 70228, Ciudad de México 04510, Mexico;
- Laboratorio de Fisiología Cardiovascular y Transplante Renal, Unidad de Investigación UNAM-INCICH, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico
| | - Eulises Díaz-Díaz
- Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y de la Nutrición “Salvador Zubirán”, Vasco de Quiroga 15, Sección XVI, Tlalpan, México City 14000, Mexico;
| | - María Esther Rubio-Ruíz
- Department of Physiology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico; (A.C.-M.); (V.C.-T.)
- Correspondence:
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15
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Wang X, Huang Y, Zhang K, Chen F, Nie T, Zhao Y, He F, Ni J. Changes of energy metabolism in failing heart and its regulation by SIRT3. Heart Fail Rev 2023:10.1007/s10741-023-10295-5. [PMID: 36708431 DOI: 10.1007/s10741-023-10295-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/11/2023] [Indexed: 01/29/2023]
Abstract
Heart failure (HF) is the leading cause of hospitalization in elderly patients and a disease with extremely high morbidity and mortality rate worldwide. Although there are some existing treatment methods for heart failure, due to its complex pathogenesis and often accompanied by various comorbidities, there is still a lack of specific drugs to treat HF. The mortality rate of patients with HF is still high, highlighting an urgent need to elucidate the pathophysiological mechanisms of HF and seek new therapeutic approaches. The heart is an organ with a very high metabolic intensity, mainly using fatty acids, glucose, ketone bodies, and branched-chain amino acids as energy substrates to supply energy for the heart. Loss of metabolic flexibility and metabolic remodeling occurs with HF. Sirtuin3 (SIRT3) is a member of the NAD+-dependent Sirtuin family located in mitochondria, and can participate in mitochondrial physiological functions through the deacetylation of metabolic and respiratory enzymes in mitochondria. As the center of energy metabolism, mitochondria are involved in many physiological processes. Maintaining stable metabolic and physiological functions of the heart depends on normal mitochondrial function. The damage or loss of SIRT3 can lead to various cardiovascular diseases. Therefore, we summarize the recent progress of SIRT3 in cardiac mitochondrial protection and metabolic remodeling.
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Affiliation(s)
- Xiao Wang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Yuting Huang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, 341000, China
| | - Kai Zhang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Feng Chen
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Tong Nie
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Yun Zhao
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Feng He
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization, Huanggang Normal University, Huanggang, 438000, China.
| | - Jingyu Ni
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
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16
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Wang L, Zabri H, Gorressen S, Semmler D, Hundhausen C, Fischer JW, Bottermann K. Cardiac ischemia modulates white adipose tissue in a depot-specific manner. Front Physiol 2022; 13:1036945. [DOI: 10.3389/fphys.2022.1036945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/13/2022] [Indexed: 11/13/2022] Open
Abstract
The incidence of heart failure after myocardial infarction (MI) remains high and the underlying causes are incompletely understood. The crosstalk between heart and adipose tissue and stimulated lipolysis has been identified as potential driver of heart failure. Lipolysis is also activated acutely in response to MI. However, the role in the post-ischemic remodeling process and the contribution of different depots of adipose tissue is unclear. Here, we employ a mouse model of 60 min cardiac ischemia and reperfusion (I/R) to monitor morphology, cellular infiltrates and gene expression of visceral and subcutaneous white adipose tissue depots (VAT and SAT) for up to 28 days post ischemia. We found that in SAT but not VAT, adipocyte size gradually decreased over the course of reperfusion and that these changes were associated with upregulation of UCP1 protein, indicating white adipocyte conversion to the so-called ‘brown-in-white’ phenotype. While this phenomenon is generally associated with beneficial metabolic consequences, its role in the context of MI is unknown. We further measured decreased lipogenesis in SAT together with enhanced infiltration of MAC-2+ macrophages. Finally, quantitative PCR analysis revealed transient downregulation of the adipokines adiponectin, leptin and resistin in SAT. While adiponectin and leptin have been shown to be cardioprotective, the role of resistin after MI needs further investigation. Importantly, all significant changes were identified in SAT, while VAT was largely unaffected by MI. We conclude that targeted interference with lipolysis in SAT may be a promising approach to promote cardiac healing after ischemia.
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17
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Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol 2021; 18:809-823. [PMID: 34127848 DOI: 10.1038/s41569-021-00569-6] [Citation(s) in RCA: 495] [Impact Index Per Article: 123.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2021] [Indexed: 12/22/2022]
Abstract
Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.
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Affiliation(s)
- David Montaigne
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Laura Butruille
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Bart Staels
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
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Karwi QG, Sun Q, Lopaschuk GD. The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity. Cells 2021; 10:cells10113259. [PMID: 34831481 PMCID: PMC8621814 DOI: 10.3390/cells10113259] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic patients is cardiovascular disease including diabetic cardiomyopathy. Therefore, understanding how diabetes increases the incidence of diabetic cardiomyopathy and how it mediates the major perturbations in cell signaling and energy metabolism should help in the development of therapeutics to prevent these perturbations. One of the significant metabolic alterations in diabetes is a marked increase in cardiac fatty acid oxidation rates and the domination of fatty acids as the major energy source in the heart. This increased reliance of the heart on fatty acids in the diabetic has a negative impact on cardiac function and structure through a number of mechanisms. It also has a detrimental effect on cardiac efficiency and worsens the energy status in diabetes, mainly through inhibiting cardiac glucose oxidation. Furthermore, accelerated cardiac fatty acid oxidation rates in diabetes also make the heart more vulnerable to ischemic injury. In this review, we discuss how cardiac energy metabolism is altered in diabetic cardiomyopathy and the impact of cardiac insulin resistance on the contribution of glucose and fatty acid to overall cardiac ATP production and cardiac efficiency. Furthermore, how diabetes influences the susceptibility of the myocardium to ischemia/reperfusion injury and the role of the changes in glucose and fatty acid oxidation in mediating these effects are also discussed.
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Affiliation(s)
- Qutuba G. Karwi
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2S2, Canada; (Q.G.K.); (Q.S.)
| | - Qiuyu Sun
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2S2, Canada; (Q.G.K.); (Q.S.)
| | - Gary D. Lopaschuk
- 423 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada
- Correspondence: ; Tel.: +1-780-492-2170; Fax: +1-780-492-9753
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19
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de Wit-Verheggen VHW, van de Weijer T. Changes in Cardiac Metabolism in Prediabetes. Biomolecules 2021; 11:1680. [PMID: 34827678 PMCID: PMC8615987 DOI: 10.3390/biom11111680] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/28/2021] [Accepted: 11/08/2021] [Indexed: 01/05/2023] Open
Abstract
In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.
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Affiliation(s)
- Vera H. W. de Wit-Verheggen
- Department of Nutrition and Movement Sciences, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands;
| | - Tineke van de Weijer
- Department of Nutrition and Movement Sciences, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands;
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
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Bae J, Paltzer WG, Mahmoud AI. The Role of Metabolism in Heart Failure and Regeneration. Front Cardiovasc Med 2021; 8:702920. [PMID: 34336958 PMCID: PMC8322239 DOI: 10.3389/fcvm.2021.702920] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/23/2021] [Indexed: 12/25/2022] Open
Abstract
Heart failure is the leading cause of death worldwide. The inability of the adult mammalian heart to regenerate following injury results in the development of systolic heart failure. Thus, identifying novel approaches toward regenerating the adult heart has enormous therapeutic potential for adult heart failure. Mitochondrial metabolism is an essential homeostatic process for maintaining growth and survival. The emerging role of mitochondrial metabolism in controlling cell fate and function is beginning to be appreciated. Recent evidence suggests that metabolism controls biological processes including cell proliferation and differentiation, which has profound implications during development and regeneration. The regenerative potential of the mammalian heart is lost by the first week of postnatal development when cardiomyocytes exit the cell cycle and become terminally differentiated. This inability to regenerate following injury is correlated with the metabolic shift from glycolysis to fatty acid oxidation that occurs during heart maturation in the postnatal heart. Thus, understanding the mechanisms that regulate cardiac metabolism is key to unlocking metabolic interventions during development, disease, and regeneration. In this review, we will focus on the emerging role of metabolism in cardiac development and regeneration and discuss the potential of targeting metabolism for treatment of heart failure.
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Affiliation(s)
- Jiyoung Bae
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
| | - Wyatt G Paltzer
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
| | - Ahmed I Mahmoud
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
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21
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Abstract
Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD+ and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.
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Affiliation(s)
- Gary D Lopaschuk
- Cardiovascular Research Centre, University of Alberta, Edmonton, Canada (G.D.L., Q.G.K.)
| | - Qutuba G Karwi
- Cardiovascular Research Centre, University of Alberta, Edmonton, Canada (G.D.L., Q.G.K.)
| | - Rong Tian
- Mitochondria and Metabolism Center, University of Washington, Seattle (R.T.)
| | - Adam R Wende
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.)
| | - E Dale Abel
- Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City (E.D.A.).,Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City (E.D.A.)
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22
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Pemafibrate suppresses oxidative stress and apoptosis under cardiomyocyte ischemia-reperfusion injury in type 1 diabetes mellitus. Exp Ther Med 2021; 21:331. [PMID: 33732304 PMCID: PMC7903427 DOI: 10.3892/etm.2021.9762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 10/14/2020] [Indexed: 12/18/2022] Open
Abstract
Diabetes mellitus accelerates the hyperglycemia susceptibility-induced injury to cardiac cells. The activation of peroxisome proliferator-activated receptor α (PPARα) decreases ischemia-reperfusion (IR) injury in animals without diabetes. Therefore, the present study hypothesized that pemafibrate may exert a protective effect on the myocardium in vivo and in vitro. A type 1 diabetes mellitus (T1DM) rat model and H9c2 cells exposed to high glucose under hypoxia and reoxygenation treatments were used in the present study. The rat model and the cells were subsequently treated with pemafibrate. In the T1DM rat model, pemafibrate enhanced the expression of PPARα in the diabetic-myocardial ischemia-reperfusion injury (D-IRI) group compared with the D-IRI group. The infarct size in the D-IRI group was reduced following pemafibrate treatment relative to the untreated group. The disruption of the mitochondrial structure and myofibrils in the D-IRI group was partially recovered by pemafibrate. In addition, to evaluate the mechanism of action of pemafibrate in the treatment of diabetic myocardial IR injury, an in vitro model was established. PPARα protein expression levels were reduced in the high glucose and hypoxia/reoxygenation (H/R) groups compared with that in the control or high glucose-treated groups. Pemafibrate treatment significantly enhanced the ATP and superoxide dismutase levels, and reduced the mitochondrial reactive oxygen species and malondialdehyde levels compared with the high glucose combined with H/R group. Furthermore, pemafibrate inhibited the expression of cytochrome c and cleaved-caspase-3, indicating its involvement in the regulation of mitochondrial apoptosis. Pemafibrate also reduced the expression of nuclear factor-κB (NF-κB), the activation of which reversed the protective effects of pemafibrate on diabetic myocardial IR injury in vitro. Taken together, these results suggested that pemafibrate may activate PPARα to protect the T1DM rat myocardium against IR injury through inhibition of NF-κB signaling.
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23
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Christofides A, Konstantinidou E, Jani C, Boussiotis VA. The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism 2021; 114:154338. [PMID: 32791172 PMCID: PMC7736084 DOI: 10.1016/j.metabol.2020.154338] [Citation(s) in RCA: 362] [Impact Index Per Article: 90.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/06/2020] [Accepted: 07/24/2020] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors of nuclear hormone receptor superfamily that regulate energy metabolism. Currently, three PPAR subtypes have been identified: PPARα, PPARγ, and PPARβ/δ. PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery and oxidative phosphorylation (OXPHOS) and regulation of energy homeostasis. In contrast, PPARγ is more important in lipogenesis and lipid synthesis, with highest expression levels in white adipose tissue (WAT). In addition to tissues regulating whole body energy homeostasis, PPARs are expressed in immune cells and have an emerging critical role in immune cell differentiation and fate commitment. In this review, we discuss the actions of PPARs in the function of the innate and the adaptive immune system and their implications in immune-mediated inflammatory conditions.
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Affiliation(s)
- Anthos Christofides
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Eirini Konstantinidou
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Chinmay Jani
- Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Mt. Auburn Hospital, Cambridge, MA 02138, United States of America
| | - Vassiliki A Boussiotis
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America.
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24
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Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. They are ligand-activated transcription factors and exist in three different isoforms, PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs regulate a variety of functions, including glucose and lipid homeostasis, inflammation, and development. They exhibit tissue and cell type-specific expression patterns and functions. Besides the established notion of the therapeutic potential of PPAR agonists for the treatment of glucose and lipid disorders, more recent data propose specific PPAR ligands as potential therapies for cardiovascular diseases. In this review, we focus on the knowledge of PPAR function in myocardial infarction, a severe pathological condition for which therapeutic use of PPAR modulation has been suggested.
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25
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PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2. Int J Mol Sci 2020; 21:ijms21197416. [PMID: 33049997 PMCID: PMC7582648 DOI: 10.3390/ijms21197416] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023] Open
Abstract
Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2.
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Yehualashet AS, Belachew TF, Kifle ZD, Abebe AM. Targeting Cardiac Metabolic Pathways: A Role in Ischemic Management. Vasc Health Risk Manag 2020; 16:353-365. [PMID: 32982263 PMCID: PMC7501978 DOI: 10.2147/vhrm.s264130] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
Among the vast number of noncommunicable diseases encountered worldwide, cardiovascular diseases accounted for about 17.8 million deaths in 2017 and ischemic heart disease (IHD) remains the single-largest cause of death in countries across all income groups. Because conventional medications are not without shortcomings and patients still refractory to these medications, scientific investigation is ongoing to advance the management of IHD, and shows a great promise for better treatment modalities, but additional research can warrant improvement in terms of the quality of life of patients. Metabolic modulation is one promising strategy for the treatment of IHD, because alterations in energy metabolism are involved in progression of the disease. Therefore, the purpose of this review was to strengthen attention toward the use of metabolic modulators and to review the current level of knowledge on cardiac energy metabolic pathways.
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Affiliation(s)
- Awgichew Shewasinad Yehualashet
- Pharmacology and Toxicology Unit, Department of Pharmacy, College of Health Sciences, Debre Berhan University, Debre Berhan, Ethiopia
| | | | - Zemene Demelash Kifle
- School of Pharmacy, Department of Pharmacology, University of Gondar, Gondar, Ethiopia
| | - Ayele Mamo Abebe
- Department of Nursing, College of Health Sciences, Debre Berhan University, Debre Berhan, Ethiopia
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27
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A directed network analysis of the cardiome identifies molecular pathways contributing to the development of HFpEF. J Mol Cell Cardiol 2020; 144:66-75. [DOI: 10.1016/j.yjmcc.2020.05.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 05/08/2020] [Indexed: 01/06/2023]
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28
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姚 玉, 曾 智, 赵 艳, 黎 土, 刘 育, 陈 荣. [Effect of Shexiang Tongxin dripping pills on coronary microcirculation disorder and cardiac dysfunction in a porcine model of myocardial ischemia-reperfusion injury]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:899-906. [PMID: 32895211 PMCID: PMC7321270 DOI: 10.12122/j.issn.1673-4254.2020.06.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Indexed: 12/08/2022]
Abstract
OBJECTIVE To investigate the mechanism by which Shexiang Tongxin dripping pills (STDP) improves coronary microcirculation disorder (CMD) and cardiac dysfunction in a porcine model of myocardial ischemia-reperfusion injury. METHODS Fourteen minipigs were randomly selected for interventional balloon occlusion of the middle left anterior descending branch to induce CMD, and another 7 pigs received sham operation. The pig models of CMD were randomized equally into the model group and STDP-treated group. All the animals were fed with common feed for 8 weeks, and in STDP-treated group, the pigs were given STDP at the daily dose of 3 mg/kg (mixed with feed) for 8 weeks. Before and at the 8th week after the operation, the pigs underwent coronary angiography and echocardiography to determine the vessel lumen diameter and TIMI frame count (CTFC). The pathologies of the myocardium and the microvessels were examined with HE staining at the 8th week. Western blotting was used to detect the expression of silencing information regulator (Sirt1), peroxidase proliferator-activated receptor-γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), extracellular signal-regulated kinase1/2 (ERKI/2), Toll-like receptor 4 (TLR4), and uncoupling protein 2 (UCP2) in myocardial tissue. RESULTS Before and at the 8th week after the operation, the diameter of the anterior descending vessel in the 3 groups did not differ significantly (P > 0.05). At the 8th week, the number of CTFC frames in the model group increased significantly compared with that in the sham-operated group, but was obviously lowered by treatment with STDP (P < 0.05). Myocardial ischemia-reperfusion injury significantly increased the interventricular septal thickness at end-diastole, left ventricular end-diastole dimension, end-diastole volume, interventricular septal thickness at end-systole and left ventricular mass at 8 weeks after the modeling (P < 0.05), but such changes were significantly alleviated by treatment with STDP (P < 0.05). STDP treatment markedly alleviated myocardial microvascular congestion, thrombosis and peripheral inflammatory cell infiltration induced by myocardial ischemia-reperfusion, but atrophy of the myocardial muscle fiber remained distinct. STDP obviously suppressed the down-regulation of Sirt1, PGC-1α, and PPARα and the up-regulation of ERK1/ 2, TLR4, and UCP2 in the myocardial tissues induced by myocardial ischemia-reperfusion injury. CONCLUSIONS STDP has anti-inflammatory effects and regulates energy metabolism in the myocardium through modulating Sirt1, PGC-1α, PPARα, ERKI/2, TLR4, and UCP2 to improve CMD and cardiac dysfunction after myocardial ischemia-reperfusion.
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Affiliation(s)
- 玉斯 姚
- />广东药科大学附属第一医院心血管内科,广东 广州 510000First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - 智桓 曾
- />广东药科大学附属第一医院心血管内科,广东 广州 510000First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - 艳群 赵
- />广东药科大学附属第一医院心血管内科,广东 广州 510000First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - 土娣 黎
- />广东药科大学附属第一医院心血管内科,广东 广州 510000First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - 育宏 刘
- />广东药科大学附属第一医院心血管内科,广东 广州 510000First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - 荣 陈
- />广东药科大学附属第一医院心血管内科,广东 广州 510000First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
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29
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Weiss-Hersh K, Garcia AL, Marosvölgyi T, Szklenár M, Decsi T, Rühl R. Saturated and monounsaturated fatty acids in membranes are determined by the gene expression of their metabolizing enzymes SCD1 and ELOVL6 regulated by the intake of dietary fat. Eur J Nutr 2019; 59:2759-2769. [PMID: 31676951 PMCID: PMC7413877 DOI: 10.1007/s00394-019-02121-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 10/16/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE We investigated the effect of dietary fats on the incorporation of saturated (SAFAs) and monounsaturated dietary fatty acids (MUFAs) into plasma phospholipids and the regulation of the expression of lipid-metabolizing enzymes in the liver. METHODS Mice were fed different diets containing commonly used dietary fats/oils (coconut fat, margarine, fish oil, sunflower oil, or olive oil) for 4 weeks (n = 6 per diet group). In a second experiment, mice (n = 6 per group) were treated for 7 days with synthetic ligands to activate specific nuclear hormone receptors (NHRs) and the hepatic gene expression of CYP26A1 was investigated. Hepatic gene expression of stearoyl-coenzyme A desaturase 1 (SCD1), elongase 6 (ELOVL6), and CYP26A1 was examined using quantitative real-time PCR (QRT-PCR). Fatty acid composition in mouse plasma phospholipids was analyzed by gas chromatography (GC). RESULTS We found significantly reduced hepatic gene expression of SCD1 and ELOVL6 after the fish oil diet compared with the other diets. This resulted in reduced enzyme-specific fatty acid ratios, e.g., 18:1n9/18:0 for SCD1 and 18:0/16:0 and 18:1n7/16:1n7 for ELOVL6 in plasma phospholipids. Furthermore, CYP26A1 a retinoic acid receptor-specific target was revealed as a new player mediating the suppressive effect of fish oil-supplemented diet on SCD1 and ELOVL6 hepatic gene expression. CONCLUSION Plasma levels of MUFAs and SAFAs strongly reflect an altered hepatic fatty acid-metabolizing enzyme expression after supplementation with different dietary fats/oils.
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Affiliation(s)
- Kathrin Weiss-Hersh
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary
| | - Ada L Garcia
- Human Nutrition, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
| | | | | | - Tamás Decsi
- Department of Paediatrics, University of Pécs, Pécs, Hungary
| | - Ralph Rühl
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.,Paprika Bioanalytics BT, Debrecen, Hungary
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30
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Karwad MA, Couch DG, Wright KL, Tufarelli C, Larvin M, Lund J, O'Sullivan SE. Endocannabinoids and endocannabinoid-like compounds modulate hypoxia-induced permeability in CaCo-2 cells via CB 1, TRPV1, and PPARα. Biochem Pharmacol 2019; 168:465-472. [PMID: 31325449 DOI: 10.1016/j.bcp.2019.07.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 07/15/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND PURPOSE We have previously reported that endocannabinoids modulate permeability in Caco-2 cells under inflammatory conditions and hypothesised in the present study that endocannabinoids could also modulate permeability in ischemia/reperfusion. EXPERIMENTAL APPROACH Caco-2 cells were grown on cell culture inserts to confluence. Trans-epithelial electrical resistance (TEER) was used to measure permeability. To generate hypoxia (0% O2), a GasPak™ EZ anaerobe pouch system was used. Endocannabinoids were applied to the apical or basolateral membrane in the presence or absence of receptor antagonists. KEY RESULTS Complete hypoxia decreased TEER (increased permeability) by ~35% after 4 h (recoverable) and ~50% after 6 h (non-recoverable). When applied either pre- or post-hypoxia, apical application of N-arachidonoyl-dopamine (NADA, via TRPV1), oleamide (OA, via TRPV1) and oleoylethanolamine (OEA, via TRPV1) inhibited the increase in permeability. Apical administration of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) worsened the permeability effect of hypoxia (both via CB1). Basolateral application of NADA (via TRPV1), OA (via CB1 and TRPV1), noladin ether (NE, via PPARα), and palmitoylethanolamine (PEA, via PPARα) restored permeability after 4 h hypoxia, whereas OEA increased permeability (via PPARα). After 6 h hypoxia, where permeability does not recover, only basolateral application PEA sustainably decreased permeability, and NE decreased permeability. CONCLUSIONS AND IMPLICATIONS A variety of endocannabinoids and endocannabinoid-like compounds modulate Caco-2 permeability in hypoxia/reoxygenation, which involves multiple targets, depending on whether the compounds are applied to the basolateral or apical membrane. CB1 antagonism and TRPV1 or PPARα agonism may represent novel therapeutic targets against several intestinal disorders associated with increased permeability.
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Affiliation(s)
- M A Karwad
- Division of Medical Sciences & Graduate Entry Medicine, School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, UK
| | - D G Couch
- Division of Medical Sciences & Graduate Entry Medicine, School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, UK
| | - K L Wright
- Division of Biomedical & Life Sciences, Faculty of Health & Medicine, Lancaster University, Lancaster, UK
| | - C Tufarelli
- Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
| | - M Larvin
- Graduate Entry Medical School and Health Research Institute, University of Limerick, Limerick, Ireland
| | - J Lund
- Division of Medical Sciences & Graduate Entry Medicine, School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, UK
| | - S E O'Sullivan
- Division of Medical Sciences & Graduate Entry Medicine, School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, UK.
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31
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Abstract
The heart consumes large amounts of energy in the form of ATP that is continuously replenished by oxidative phosphorylation in mitochondria and, to a lesser extent, by glycolysis. To adapt the ATP supply efficiently to the constantly varying demand of cardiac myocytes, a complex network of enzymatic and signalling pathways controls the metabolic flux of substrates towards their oxidation in mitochondria. In patients with heart failure, derangements of substrate utilization and intermediate metabolism, an energetic deficit, and oxidative stress are thought to underlie contractile dysfunction and the progression of the disease. In this Review, we give an overview of the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure and diabetes mellitus. Although the energetic deficit in failing hearts - discovered >2 decades ago - might account for contractile dysfunction during maximal exertion, we suggest that the alterations of intermediate substrate metabolism and oxidative stress rather than an ATP deficit per se account for maladaptive cardiac remodelling and dysfunction under resting conditions. Treatments targeting substrate utilization and/or oxidative stress in mitochondria are currently being tested in patients with heart failure and might be promising tools to improve cardiac function beyond that achieved with neuroendocrine inhibition.
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32
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Tutunchi H, Ostadrahimi A, Saghafi-Asl M, Maleki V. The effects of oleoylethanolamide, an endogenous PPAR-α agonist, on risk factors for NAFLD: A systematic review. Obes Rev 2019; 20:1057-1069. [PMID: 31111657 DOI: 10.1111/obr.12853] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/04/2019] [Accepted: 03/04/2019] [Indexed: 12/15/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Recently, some novel compounds have been investigated for the prevention and treatment of NAFLD. Oleoylethanolamide (OEA), an endogenous PPAR-α agonist, has exhibited a plethora of pharmacological properties for the treatment of obesity and other obesity-associated metabolic complications. This systematic review was performed with a focus on the effects of OEA on the risk factors for NAFLD. PubMed, Scopus, Embase, ProQuest, and Google Scholar databases were searched up to December 2018 using relevant keywords. All articles written in English evaluating the effects of OEA on the risk factors for NAFLD were eligible for the review. The evidence reviewed in this article illustrates that OEA regulates multiple biological processes associated with NAFLD, including lipid metabolism, inflammation, oxidative stress, and energy homeostasis through different mechanisms. In summary, many beneficial effects of OEA have led to the understanding that OEA may be an effective therapeutic strategy for the management of NAFLD. Although a wide range of studies have demonstrated the most useful effects of OEA on NAFLD and the associated risk factors, further clinical trials, from both in vivo studies and in vitro experiments, are warranted to verify these outcomes.
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Affiliation(s)
- Helda Tutunchi
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Saghafi-Asl
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Maleki
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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33
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Elshazly S, Soliman E. PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury. Toxicol Appl Pharmacol 2019; 362:86-94. [PMID: 30393147 DOI: 10.1016/j.taap.2018.10.022] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 10/16/2018] [Accepted: 10/24/2018] [Indexed: 01/09/2023]
Abstract
Remote organ damage is the major cause of death in patients with acute kidney injury (AKI) due to renal ischemia reperfusion (IR). Liver is one of the vital organs which are profoundly affected by AKI. The present study aims to investigate the role of peroxisome proliferator activator receptor gamma (PPARγ) in liver damage induced by IR injury in rats. Renal IR was induced by right nephrectomy, occlusion of left renal pedicle for 45 min to induce ischemia, and then reperfusion for 6 or 24 h. The PPARγ agonist, pioglitazone, was given orally for 7 days before renal IR procedure. Animals receiving pioglitazone showed improvement in renal and hepatic functions when compared to IR groups. Renal IR increased renal, hepatic and serum levels of tumor necrosis factor-α (TNF-α) and induced apoptotic cell death in liver. These effects were diminished with pioglitazone. In addition, pioglitazone reduced renal IR-induced oxidative stress in liver. Pioglitazone reduced malondialdehyde (MDA) content and NADPH oxidase mRNA expression and induced further increase in nuclear factor erythroid 2-related factor 2 (Nrf2) expression when compared to IR groups. Furthermore, pioglitazone increased the expression of PPARγ target genes such as renal and hepatic PPARγ1 (Pparg1), hepatic hemoxygenase-1 (Hmox1), and hepatic thioredoxin (TRx). Histological profiles for kidney and liver were also ameliorated with pioglitazone. Hence, PPARγ is a potential target to protect liver in patients with renal IR injury.
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Affiliation(s)
- Shimaa Elshazly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Eman Soliman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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The lncRNA H19/miR-675 axis regulates myocardial ischemic and reperfusion injury by targeting PPARα. Mol Immunol 2019; 105:46-54. [DOI: 10.1016/j.molimm.2018.11.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 10/24/2018] [Accepted: 11/14/2018] [Indexed: 12/21/2022]
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Zhao Q, Cui Z, Zheng Y, Li Q, Xu C, Sheng X, Tao M, Xu H. Fenofibrate protects against acute myocardial I/R injury in rat by suppressing mitochondrial apoptosis as decreasing cleaved caspase-9 activation. Cancer Biomark 2018; 19:455-463. [PMID: 28582851 DOI: 10.3233/cbm-170572] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND AIMS Peroxisome proliferator-activated receptor-α (PPAR-α) activation has been reported to reduce myocardial ischemia-reperfusion (I/R) injury by inhibiting cell apoptosis. However, the antiapoptotic mechanism of PPAR-α is still unknown. Fenofibrate is a PPAR-α agonist In the present study, we investigate the effects and relevant mechanism of fenofibrate on experimental myocardial ischemia-reperfusion (I/R) injury in rats. METHODS Adult male Wistar rats were pretreated with fenofibrate (80 mg/kg) daily for a period of 7 days. After the treatment period, myocardial I/R injury model was made by left anterior descending coronary artery ligation for 45 min and reperfusion for 120 min. Myocardial infarct size, malondialdehyde (MDA) cleaved-caspase-9 protein expression, PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue were detected Cell apoptosis was detected by Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Serum lactate dehydrogenase and creatine kinase activities were measured in rats pretreated with fenofibrate The ultrastructure of myocardial tissues was observed. RESULTS Significant increases in myocardial cell apoptosis, malondialdehyde (MDA) level and cleaved-caspase-9 protein expression level in myocardial tissue were observed, along with reductions of PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue of the experimental myocardial ischemia-reperfusion (I/R) injury in rats. Impaired mitochondria were also observed under electron microscopic. However, pretreatment of ischemia/reperfusion rats with fenofibrate brought the biochemical parameters and related genes expression levels to near normalcy, indicating the protective effect of fenofibrate against myocardial ischemia/reperfusion injury in rats. CONCLUSIONS The PPAR-α activator fenofibrate conferred cytoprotective effect against myocardial ischemia-reperfusion (I/R) injury in rats. Associated mechanisms involved decreased cleaved-caspase-9 expression and decreased cell apoptosis.
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Affiliation(s)
- Qing Zhao
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zheng Cui
- Department of Endoscope, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yan Zheng
- Department of Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Qun Li
- Department of Endoscope, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Changyuan Xu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xueqi Sheng
- Department of Endoscope, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Mei Tao
- Department of Endoscope, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - HuiXin Xu
- Department of Endoscope, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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Oikonomou E, Mourouzis K, Fountoulakis P, Papamikroulis GA, Siasos G, Antonopoulos A, Vogiatzi G, Tsalamadris S, Vavuranakis M, Tousoulis D. Interrelationship between diabetes mellitus and heart failure: the role of peroxisome proliferator-activated receptors in left ventricle performance. Heart Fail Rev 2018; 23:389-408. [PMID: 29453696 DOI: 10.1007/s10741-018-9682-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Heart failure (HF) is a common cardiac syndrome, whose pathophysiology involves complex mechanisms, some of which remain unknown. Diabetes mellitus (DM) constitutes not only a glucose metabolic disorder accompanied by insulin resistance but also a risk factor for cardiovascular disease and HF. During the last years though emerging data set up, a bidirectional interrelationship between these two entities. In the case of DM impaired calcium homeostasis, free fatty acid metabolism, redox state, and advance glycation end products may accelerate cardiac dysfunction. On the other hand, when HF exists, hypoperfusion of the liver and pancreas, b-blocker and diuretic treatment, and autonomic nervous system dysfunction may cause impairment of glucose metabolism. These molecular pathways may be used as therapeutic targets for novel antidiabetic agents. Peroxisome proliferator-activated receptors (PPARs) not only improve insulin resistance and glucose and lipid metabolism but also manifest a diversity of actions directly or indirectly associated with systolic or diastolic performance of left ventricle and symptoms of HF. Interestingly, they may beneficially affect remodeling of the left ventricle, fibrosis, and diastolic performance but they may cause impaired water handing, sodium retention, and decompensation of HF which should be taken into consideration in the management of patients with DM. In this review article, we present the pathophysiological data linking HF with DM and we focus on the molecular mechanisms of PPARs agonists in left ventricle systolic and diastolic performance providing useful insights in the molecular mechanism of this class of metabolically active regiments.
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Affiliation(s)
- Evangelos Oikonomou
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece.
| | - Konstantinos Mourouzis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Petros Fountoulakis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Georgios Angelos Papamikroulis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Gerasimos Siasos
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Alexis Antonopoulos
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Georgia Vogiatzi
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Sotiris Tsalamadris
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Manolis Vavuranakis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
| | - Dimitris Tousoulis
- 1st Department of Cardiology, 'Hippokration' Hospital, National and Kapodistrian University of Athens Medical School, Vasilissis Sofias 114, TK, 115 28, Athens, Greece
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Protective Effects of Ultramicronized Palmitoylethanolamide (PEA-um) in Myocardial Ischaemia and Reperfusion Injury in VIVO. Shock 2018; 46:202-13. [PMID: 26844976 DOI: 10.1097/shk.0000000000000578] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Myocardial infarction is the leading cause of death, occurs after prolonged ischemia of the coronary arteries. Restore blood flow is the first intervention help against heart attack. However, reperfusion of the arteries leads to ischemia/reperfusion injury (I/R). The fatty acid amide palmitoylethanolamide (PEA) is an endogenous compound widely present in living organisms, with analgesic and anti-inflammatory properties. The present study evaluated the effect of ultramicronized palmitoylethanolamide (PEA-um) treatment on the inflammatory process associated with myocardial I/R. Myocardial ischemia reperfusion injury was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. PEA-um, was administered (10 mg/kg) 15 min after ischemia and 1 h after reperfusion. In this study, we demonstrated that PEA-um treatment reduces myocardial tissue injury, neutrophil infiltration, adhesion molecules (ICAM-1, P-selectin) expression, proinflammatory cytokines (TNF-α, IL-1β) production, nitrotyrosine and PAR formation, nuclear factor kB expression, and apoptosis (Fas-L, Bcl-2) activation. In addition to study whether the protective effect of PEA-um on myocardial ischemia reperfusion injury is also related to the activation of PPAR-α, in a separate set of experiments it has been performed myocardial I/R in PPARα mice. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated Myocardial ischemia reperfusion injury when compared with PPAR-αWT mice. PEA-um induced cardioprotection in PPAR-α wild-type mice, but the same effect cannot be observed in PPAR-αKO mice. Our results have clearly shown a modulation of the inflammatory process, associated with myocardial ischemia reperfusion injury, following administration of PEA-um.
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Khan V, Sharma S, Bhandari U, Ali SM, Haque SE. Raspberry ketone protects against isoproterenol-induced myocardial infarction in rats. Life Sci 2017; 194:205-212. [PMID: 29225109 DOI: 10.1016/j.lfs.2017.12.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 11/28/2017] [Accepted: 12/06/2017] [Indexed: 12/12/2022]
Abstract
AIM The cardioprotective role of raspberry ketone (RK) against isoproterenol (ISO)-induced myocardial infarction (MI) in rats was assessed. MATERIALS AND METHODS Rats were randomly divided into Group I - Vehicle control; Group II - Toxic control ISO (85mg/kg, s.c.); Group III, IV and V - RK (50, 100 and 200mg/kg, respectively) with ISO; Group VI- RK (200mg/kg) alone; Group VII - Propranolol (10mg/kg) with ISO; and Group VIII - Propranolol (10mg/kg) alone. After twenty-four hours of the last dose, animals were sacrificed and creatine kinase-MB, lactate dehydrogenase, total cholesterol, triglycerides, high-density-lipoprotein, low-density-lipoprotein, very-low-density-lipoprotein, malondialdehyde, reduced glutathione, superoxide dismutase, catalase, Na+, K+-ATPase, nitric oxide, histopathological and immunohistochemical analysis (tumor necrosis factor-α and inducible nitric oxide synthase) were performed. KEY FINDINGS Treatment with ISO significantly deviated the biochemical parameters from the normal levels, which were considerably restored by RK at 100 and 200mg/kg doses. 50mg/kg dose, however, did not demonstrate any significant cardioprotective action. The histopathological and immunohistochemical analysis further substantiated these findings. SIGNIFICANCE Our study showed a dose-dependent reduction in oxidative stress, inflammation and dyslipidemia by RK in ISO-intoxicated rats, which signifies that RK from the European red raspberry plant might be a valuable entity for the management of MI.
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Affiliation(s)
- Vasim Khan
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Sumit Sharma
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Uma Bhandari
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Syed Mansoor Ali
- Department of Biotechnology, Jamia Milia Islamia, New Delhi 110025, India
| | - Syed Ehtaishamul Haque
- Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi 110062, India.
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Abushouk AI, El-Husseny MWA, Bahbah EI, Elmaraezy A, Ali AA, Ashraf A, Abdel-Daim MM. Peroxisome proliferator-activated receptors as therapeutic targets for heart failure. Biomed Pharmacother 2017; 95:692-700. [PMID: 28886529 DOI: 10.1016/j.biopha.2017.08.083] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/05/2017] [Accepted: 08/23/2017] [Indexed: 01/06/2023] Open
Abstract
Heart failure (HF) is a common clinical syndrome that affects more than 23 million individuals worldwide. Despite the marked advances in its management, the mortality rates in HF patients have remained unacceptably high. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription regulators, involved in the regulation of fatty acid and glucose metabolism. PPAR agonists are currently used for the treatment of type II diabetes mellitus and hyperlipidemia; however, their role as therapeutic agents for HF remains under investigation. Preclinical studies have shown that pharmacological modulation of PPARs can upregulate the expression of fatty acid oxidation genes in cardiomyocytes. Moreover, PPAR agonists were proven able to improve ventricular contractility and reduce cardiac remodelling in animal models through their anti-inflammatory, anti-oxidant, anti-fibrotic, and anti-apoptotic activities. Whether these effects can be replicated in humans is yet to be proven. This article reviews the interactions of PPARs with the pathophysiological mechanisms of HF and how the pharmacological modulation of these receptors can be of benefit for HF patients.
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Affiliation(s)
| | | | - Eshak I Bahbah
- Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Ahmed Elmaraezy
- NovaMed Medical Research Association, Cairo, Egypt; Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Aya Ashraf Ali
- Faculty of Medicine, Minia University, Minia, Egypt; Minia Medical Research Society, Minia University, Minia, Egypt
| | - Asmaa Ashraf
- Faculty of Medicine, Minia University, Minia, Egypt; Minia Medical Research Society, Minia University, Minia, Egypt
| | - Mohamed M Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt; Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan.
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Affiliation(s)
- Samuel O. Adeosun
- Department of Physiology & Biophysics, Mississippi Center
for Obesity Research, University of Mississippi Medical Center, 2500 North State St,
Jackson, MS 39216
| | - David E. Stec
- Department of Physiology & Biophysics, Mississippi Center
for Obesity Research, University of Mississippi Medical Center, 2500 North State St,
Jackson, MS 39216
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Slezak J, Kura B, Babal P, Barancik M, Ferko M, Frimmel K, Kalocayova B, Kukreja RC, Lazou A, Mezesova L, Okruhlicova L, Ravingerova T, Singal PK, Szeiffova Bacova B, Viczenczova C, Vrbjar N, Tribulova N. Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury. Can J Physiol Pharmacol 2017; 95:1190-1203. [PMID: 28750189 DOI: 10.1139/cjpp-2017-0121] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Irradiation of normal tissues leads to acute increase in reactive oxygen/nitrogen species that serve as intra- and inter-cellular signaling to alter cell and tissue function. In the case of chest irradiation, it can affect the heart, blood vessels, and lungs, with consequent tissue remodelation and adverse side effects and symptoms. This complex process is orchestrated by a large number of interacting molecular signals, including cytokines, chemokines, and growth factors. Inflammation, endothelial cell dysfunction, thrombogenesis, organ dysfunction, and ultimate failing of the heart occur as a pathological entity - "radiation-induced heart disease" (RIHD) that is major source of morbidity and mortality. The purpose of this review is to bring insights into the basic mechanisms of RIHD that may lead to the identification of targets for intervention in the radiotherapy side effect. Studies of authors also provide knowledge about how to select targeted drugs or biological molecules to modify the progression of radiation damage in the heart. New prospective studies are needed to validate that assessed factors and changes are useful as early markers of cardiac damage.
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Affiliation(s)
- Jan Slezak
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Branislav Kura
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Pavel Babal
- b Institute of Pathology, Medical Faculty of Comenius University, Bratislava, Slovakia
| | - Miroslav Barancik
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Miroslav Ferko
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Karel Frimmel
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Barbora Kalocayova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Rakesh C Kukreja
- c Division of Cardiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
| | - Antigone Lazou
- d School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Lucia Mezesova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Ludmila Okruhlicova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Tanya Ravingerova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Pawan K Singal
- e University of Manitoba, St. Boniface Research Centre, Winnipeg, MB R2H 2A6, Canada
| | | | - Csilla Viczenczova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Norbert Vrbjar
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Narcis Tribulova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
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Ravingerová T, Farkašová V, Griecsová L, Muráriková M, Carnická S, Lonek L, Ferko M, Slezak J, Zálešák M, Adameova A, Khandelwal VKM, Lazou A, Kolar F. Noninvasive approach to mend the broken heart: Is "remote conditioning" a promising strategy for application in humans? Can J Physiol Pharmacol 2017; 95:1204-1212. [PMID: 28683229 DOI: 10.1139/cjpp-2017-0200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Currently, there are no satisfactory interventions to protect the heart against the detrimental effects of ischemia-reperfusion injury. Although ischemic preconditioning (PC) is the most powerful form of intrinsic cardioprotection, its application in humans is limited to planned interventions, due to its short duration and technical requirements. However, many organs/tissues are capable of producing "remote" PC (RPC) when subjected to brief bouts of ischemia-reperfusion. RPC was first described in the heart where brief ischemia in one territory led to protection in other area. Later on, RPC started to be used in patients with acute myocardial infarction, albeit with ambiguous results. It is hypothesized that the connection between the signal triggered in remote organ and protection induced in the heart can be mediated by humoral and neural pathways, as well as via systemic response to short sublethal ischemia. However, although RPC has a potentially important clinical role, our understanding of the mechanistic pathways linking the local stimulus to the remote organ remains incomplete. Nevertheless, RPC appears as a cost-effective and easily performed intervention. Elucidation of protective mechanisms activated in the remote organ may have therapeutic and diagnostic implications in the management of myocardial ischemia and lead to development of pharmacological RPC mimetics.
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Affiliation(s)
- Táňa Ravingerová
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Veronika Farkašová
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lucia Griecsová
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Martina Muráriková
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Slavka Carnická
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - L'ubomír Lonek
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Miroslav Ferko
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jan Slezak
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Marek Zálešák
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Adriana Adameova
- b Faculty of Pharmacy, Comenius University, Bratislava, Slovakia
| | | | - Antigone Lazou
- d School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Frantisek Kolar
- e Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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Neuhaus W, Krämer T, Neuhoff A, Gölz C, Thal SC, Förster CY. Multifaceted Mechanisms of WY-14643 to Stabilize the Blood-Brain Barrier in a Model of Traumatic Brain Injury. Front Mol Neurosci 2017; 10:149. [PMID: 28603485 PMCID: PMC5445138 DOI: 10.3389/fnmol.2017.00149] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 05/03/2017] [Indexed: 12/27/2022] Open
Abstract
The blood-brain barrier (BBB) is damaged during ischemic insults such as traumatic brain injury or stroke. This contributes to vasogenic edema formation and deteriorate disease outcomes. Enormous efforts are pursued to understand underlying mechanisms of ischemic insults and develop novel therapeutic strategies. In the present study the effects of PPARα agonist WY-14643 were investigated to prevent BBB breakdown and reduce edema formation. WY-14643 inhibited barrier damage in a mouse BBB in vitro model of traumatic brain injury based on oxygen/glucose deprivation in a concentration dependent manner. This was linked to changes of the localization of tight junction proteins. Furthermore, WY-14643 altered phosphorylation of kinases ERK1/2, p38, and SAPK/JNK and was able to inhibit proteosomal activity. Moreover, addition of WY-14643 upregulated PAI-1 leading to decreased t-PA activity. Mouse in vivo experiments showed significantly decreased edema formation in a controlled cortical impact model of traumatic brain injury after WY-14643 application, which was not found in PAI-1 knockout mice. Generally, data suggested that WY-14643 induced cellular responses which were dependent as well as independent from PPARα mediated transcription. In conclusion, novel mechanisms of a PPARα agonist were elucidated to attenuate BBB breakdown during traumatic brain injury in vitro.
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Affiliation(s)
- Winfried Neuhaus
- Competence Unit Molecular Diagnostics, Competence Center Health and Bioresources, AIT Austrian Institute of Technology (AIT) GmbHVienna, Austria
| | - Tobias Krämer
- Department of Anesthesiology, Medical Center of Johannes Gutenberg University of MainzMainz, Germany
| | - Anja Neuhoff
- Department of Anesthesia and Critical Care, Center of Operative Medicine, University Hospital WürzburgWürzburg, Germany
| | - Christina Gölz
- Department of Anesthesiology, Medical Center of Johannes Gutenberg University of MainzMainz, Germany
| | - Serge C Thal
- Department of Anesthesiology, Medical Center of Johannes Gutenberg University of MainzMainz, Germany
| | - Carola Y Förster
- Department of Anesthesia and Critical Care, Center of Operative Medicine, University Hospital WürzburgWürzburg, Germany
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Chen Y, Chen H, Birnbaum Y, Nanhwan MK, Bajaj M, Ye Y, Qian J. Aleglitazar, a dual peroxisome proliferator-activated receptor-α and -γ agonist, protects cardiomyocytes against the adverse effects of hyperglycaemia. Diab Vasc Dis Res 2017; 14:152-162. [PMID: 28111985 PMCID: PMC5305042 DOI: 10.1177/1479164116679081] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
PURPOSE To assess the effects of Aleglitazar on hyperglycaemia-induced apoptosis. METHODS We incubated human cardiomyocytes, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout or wild-type mice in normoglycaemic or hyperglycaemic conditions (glucose 25 mM). Cells were treated with different concentrations of Aleglitazar for 48 h. We measured viability, apoptosis, caspase-3 activity, cytochrome-C release, total antioxidant capacity and reactive oxygen species formation in the treated cardiomyocytes. Human cardiomyocytes were transfected with short interfering RNA against peroxisome proliferator-activated receptor-α or peroxisome proliferator-activated receptor-γ. RESULTS Aleglitazar attenuated hyperglycaemia-induced apoptosis, caspase-3 activity and cytochrome-C release and increased viability in human cardiomyocyte, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout and wild-type mice. Hyperglycaemia reduced the antioxidant capacity and Aleglitazar significantly blunted this effect. Hyperglycaemia-induced reactive oxygen species production was attenuated by Aleglitazar in both human cardiomyocyte and wild-type mice cardiomyocytes. Aleglitazar improved cell viability in cells exposed to hyperglycaemia. The protective effect was partially blocked by short interfering RNA against peroxisome proliferator-activated receptor-α alone and short interfering RNA against peroxisome proliferator-activated receptor-γ alone and completely blocked by short interfering RNA to both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ. CONCLUSION Aleglitazar protects cardiomyocytes against hyperglycaemia-induced apoptosis by combined activation of both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ in a short-term vitro model.
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Affiliation(s)
- Yan Chen
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hongmei Chen
- Department of Anesthesiology, Kunming Tongren Hospital, Kunming, China
| | - Yochai Birnbaum
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Manjyot K Nanhwan
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Mandeep Bajaj
- Section of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Yumei Ye
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Jinqiao Qian
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Jinqiao Qian, Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, #295 Xichang Road, Kunming 650032, Yunnan Province, China.
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Tapio S. Using proteomics to explore the effects of radiation on the heart - impacts for medicine. Expert Rev Proteomics 2017; 14:277-279. [DOI: 10.1080/14789450.2017.1294067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Soile Tapio
- Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Institute of Radiation Biology, Neuherberg, Germany
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Zhang J, Cheng Y, Gu J, Wang S, Zhou S, Wang Y, Tan Y, Feng W, Fu Y, Mellen N, Cheng R, Ma J, Zhang C, Li Z, Cai L. Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice. Clin Sci (Lond) 2016; 130:625-641. [PMID: 26795437 DOI: 10.1042/cs20150623] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 01/21/2016] [Indexed: 02/02/2023]
Abstract
Fenofibrate (FF), as a peroxisome-proliferator-activated receptor α (PPARα) agonist, has been used clinically for decades to lower lipid levels. In the present study, we examined whether FF can be repurposed to prevent the pathogenesi of the heart in Type 1 diabetes and to describe the underlying mechanism of its action. Streptozotocin (STZ)-induced diabetic mice and their age-matched control mice were treated with vehicle or FF by gavage every other day for 3 or 6 months. FF prevented diabetes-induced cardiac dysfunction (e.g. decreased ejection fraction and hypertrophy), inflammation and remodelling. FF also increased cardiac expression of fibroblast growth factor 21 (FGF21) and sirtuin 1 (Sirt1) in non-diabetic and diabetic conditions. Deletion of FGF21 gene (FGF21-KO) worsened diabetes-induced pathogenic effects in the heart. FF treatment prevented heart deterioration in the wild-type diabetic mice, but could not do so in the FGF21-KO diabetic mice although the systemic lipid profile was lowered in both wild-type and FGF21-KO diabetic mice. Mechanistically, FF treatment prevented diabetes-impaired autophagy, reflected by increased microtubule-associated protein 1A/1B-light chain 3, in the wild-type diabetic mice but not in the FGF21-KO diabetic mice. Studies with H9C2 cells in vitro demonstrated that exposure to high glucose (HG) significantly increased inflammatory response, oxidative stress and pro-fibrotic response and also significantly inhibited autophagy. These effects of HG were prevented by FF treatment. Inhibition of either autophagy by 3-methyladenine (3MA) or Sirt1 by sirtinol (SI) abolished FF's prevention of HG-induced effects. These results suggested that FF could prevent Type 1 diabetes-induced pathological and functional abnormalities of the heart by increasing FGF21 that may up-regulate Sirt1-mediated autophagy.
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MESH Headings
- Animals
- Autophagy/drug effects
- Blood Glucose/metabolism
- Cell Line
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/enzymology
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/enzymology
- Diabetes Mellitus, Type 1/pathology
- Diabetic Cardiomyopathies/enzymology
- Diabetic Cardiomyopathies/etiology
- Diabetic Cardiomyopathies/pathology
- Diabetic Cardiomyopathies/physiopathology
- Diabetic Cardiomyopathies/prevention & control
- Fenofibrate/pharmacology
- Fibroblast Growth Factors/deficiency
- Fibroblast Growth Factors/genetics
- Fibroblast Growth Factors/metabolism
- Fibrosis
- Histone Deacetylase Inhibitors/pharmacology
- Hypertrophy, Left Ventricular/enzymology
- Hypertrophy, Left Ventricular/pathology
- Hypertrophy, Left Ventricular/prevention & control
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Myocarditis/enzymology
- Myocarditis/etiology
- Myocarditis/pathology
- Myocarditis/physiopathology
- Myocarditis/prevention & control
- Myocardium/enzymology
- Myocardium/pathology
- Oxidative Stress/drug effects
- Rats
- Signal Transduction/drug effects
- Sirtuin 1/metabolism
- Time Factors
- Ventricular Function, Left/drug effects
- Ventricular Remodeling/drug effects
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Affiliation(s)
- Jingjing Zhang
- Department of Cardiology at the First Hospital of China Medical University, and Department of Cardiology at the People's Hospital of Liaoning Province, Shenyang 110016, China The Chinese-American Research Institute for Diabetic Complications, the Wenzhou Medical University, Wenzhou 325035, China Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A
| | - Yanli Cheng
- Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A. The First Hospital of Jilin University, Changchun 130021, China
| | - Junlian Gu
- Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A
| | - Shudong Wang
- Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A. The First Hospital of Jilin University, Changchun 130021, China
| | - Shanshan Zhou
- Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A. The First Hospital of Jilin University, Changchun 130021, China
| | - Yuehui Wang
- The First Hospital of Jilin University, Changchun 130021, China
| | - Yi Tan
- The Chinese-American Research Institute for Diabetic Complications, the Wenzhou Medical University, Wenzhou 325035, China Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A. Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A
| | - Wenke Feng
- Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A
| | - Yaowen Fu
- The First Hospital of Jilin University, Changchun 130021, China
| | - Nicholas Mellen
- Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A
| | - Rui Cheng
- Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A
| | - Jianxing Ma
- Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A
| | - Chi Zhang
- The Chinese-American Research Institute for Diabetic Complications, the Wenzhou Medical University, Wenzhou 325035, China
| | - Zhanquan Li
- Department of Cardiology at the First Hospital of China Medical University, and Department of Cardiology at the People's Hospital of Liaoning Province, Shenyang 110016, China
| | - Lu Cai
- The Chinese-American Research Institute for Diabetic Complications, the Wenzhou Medical University, Wenzhou 325035, China Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A. Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A.
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Chang H, Wang Q, Shi T, Huo K, Li C, Zhang Q, Wang G, Wang Y, Tang B, Wang W, Wang Y. Effect of DanQi Pill on PPARα, lipid disorders and arachidonic acid pathway in rat model of coronary heart disease. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:103. [PMID: 27000070 PMCID: PMC4802898 DOI: 10.1186/s12906-016-1083-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 03/16/2016] [Indexed: 12/13/2022]
Abstract
Background Danqi pill (DQP) is one of the most widely prescribed formulas and has been shown to have remarkable protective effect on coronary heart disease (CHD). However, its regulatory effects on lipid metabolism disorders haven’t been comprehensively studied so far. We aimed to explore the effects of DQP on Peroxisome Proliferator activated receptors α (PPARα), lipid uptake-transportation-metabolism pathway and arachidonic acid (AA)-mediated inflammation pathway in rats with CHD. Methods 80 Sprague-Dawley (SD) Rats were randomly divided into sham group, model group, positive control group and DQP group. Rat model of CHD was induced by ligation of left ventricle anterior descending artery and fed with high fat diet in all but the sham group. Rats in sham group only underwent thoracotomy. After surgery, rats in the positive control and DQP group received daily treatments of pravastatin and DQP respectively. At 28 days after surgery, rats were sacrificed and plasma lipids were evaluated by plasma biochemical detection. Western blot and PCR were applied to evaluate the expressions of PPARα, proteins involved in lipid metabolism and AA pathways. Results Twenty eight days after surgery, dyslipidemia developed in CHD model rats, as illustrated by elevated plasma lipid levels. Expressions of apolipoprotein A-I (ApoA-I), cluster of differentiation 36 (CD36) and fatty acid binding protein (FABP) in the heart tissues of model group were down-regulated compared with those in sham group. Expressions of carnitine palmitoyl transferase I (CPT-1A) and lipoproteinlipase (LPL) were also reduced significantly. In addition, levels of phospholipase A2 (PLA2) and cyclooxygenase 2 (COX-2) were up-regulated. Expressions of Nuclear factor-κB (NF- κB) and signal transducer and activator of transcription 3 (STAT3) also increased. Furthermore, Expression of PPARα decreased in the model group. DQP significantly up-regulated expressions of ApoA-I and FABP, as well as the expressions of CPT-1A and CD36. In addition, DQP down-regulated expressions of PLA2, COX-2 and NF-κB in inflammation pathway. Levels of STAT3 and LPL were not affected by DQP treatment. In particular, DQP up-regulated PPARα level significantly. Conclusions DQP could effectively regulate lipid uptake-transportation-metabolism process in CHD model rats, and the effect is achieved mainly by activating ApoA-I-CD36-CPT-1A molecules. Interestingly, DQP can up-regulate expression of PPARα significantly. The anti-inflammatory effect of DQP is partly exerted by inhibiting expressions of PLA2-COX2 -NF-κB pathway.
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Involvement of Inflammatory Cytokines in Antiarrhythmic Effects of Clofibrate in Ouabain-Induced Arrhythmia in Isolated Rat Atria. Adv Pharmacol Sci 2016; 2016:9128018. [PMID: 26977143 PMCID: PMC4764719 DOI: 10.1155/2016/9128018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 01/06/2016] [Accepted: 01/13/2016] [Indexed: 11/18/2022] Open
Abstract
Considering the cardioprotective and anti-inflammatory properties of clofibrate, the aim of the present experiment was to investigate the involvement of local and systemic inflammatory cytokines in possible antiarrhythmic effects of clofibrate in ouabain-induced arrhythmia in rats. Rats were orally treated with clofibrate (300 mg/kg), and ouabain (0.56 mg/kg) was administered to animals intraperitoneally. After induction of anesthesia, the atria were isolated and the onset of arrhythmia and asystole was recorded. The levels of inflammatory cytokines in atria were also measured. Clofibrate significantly postponed the onset of arrhythmia and asystole when compared to control group (P ≤ 0.05 and P ≤ 0.01, resp.). While ouabain significantly increased the atrial beating rate in control group (P ≤ 0.05), same treatment did not show similar effect in clofibrate-treated group (P > 0.05). Injection of ouabain significantly increased the atrial and systemic levels of all studied inflammatory cytokines (P ≤ 0.05). Pretreatment with clofibrate could attenuate the ouabain-induced elevation of IL-6 and TNF-α in atria (P ≤ 0.01 and P ≤ 0.05, resp.), as well as ouabain-induced increase in IL-6 in plasma (P ≤ 0.05). Based on our findings, clofibrate may possess antiarrhythmic properties through mitigating the local and systemic inflammatory factors including IL-6 and TNF-α.
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Fenofibrate plus Metformin Produces Cardioprotection in a Type 2 Diabetes and Acute Myocardial Infarction Model. PPAR Res 2016; 2016:8237264. [PMID: 27069466 PMCID: PMC4812489 DOI: 10.1155/2016/8237264] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 02/18/2016] [Indexed: 11/17/2022] Open
Abstract
We investigated whether fenofibrate, metformin, and their combination generate cardioprotection in a rat model of type 2 diabetes (T2D) and acute myocardial infarction (AMI). Streptozotocin-induced diabetic- (DB-) rats received 14 days of either vehicle, fenofibrate, metformin, or their combination and immediately after underwent myocardial ischemia/reperfusion (I/R). Fenofibrate plus metformin generated cardioprotection in a DBI/R model, reported as decreased coronary vascular resistance, compared to DBI/R-Vehicle, smaller infarct size, and increased cardiac work. The subchronic treatment with fenofibrate plus metformin increased, compared with DBI/R-Vehicle, total antioxidant capacity, manganese-dependent superoxide dismutase activity (MnSOD), guanosine triphosphate cyclohydrolase I (GTPCH-I) expression, tetrahydrobiopterin : dihydrobiopterin (BH4 : BH2) ratio, endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO) bioavailability, and decreased inducible NOS (iNOS) activity. These findings suggest that PPARα activation by fenofibrate + metformin, at low doses, generates cardioprotection in a rat model of T2D and AMI and may represent a novel treatment strategy to limit I/R injury in patients with T2D.
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Feng X, Gao X, Jia Y, Zhang H, Xu Y, Wang G. PPAR-α Agonist Fenofibrate Decreased RANTES Levels in Type 2 Diabetes Patients with Hypertriglyceridemia. Med Sci Monit 2016; 22:743-51. [PMID: 26944934 PMCID: PMC4784549 DOI: 10.12659/msm.897307] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Regulated upon activation, normal T cells expressed and secreted (RANTES) is associated with inflammation and atherosclerosis. We investigated the effect of fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, on RANTES in type 2 diabetes mellitus (T2DM) patients with hypertriglyceridemia. Material/Methods This study evaluated cross-sectional and interventional studies of 25 T2DM patients with hypertriglyceridemia (group A) and 32 controls (group B). Group A was treated with fenofibrate (200 mg/day) for 8 weeks. Serum RANTES and clinical characteristics were examined. Results Serum RANTES was significantly higher in group A compared with group B (59.04±16.74 vs. 38.57±12.98 ng/ml, P<0.001) and correlated with triglycerides (TG) (r=0.535, P<0.001), fasting blood glucose (FBG) (r=0.485, P<0.001), glycosylated hemoglobin (HbA1c) (r=0.485, P<0.001), homocysteine (Hcy) (r=0.520, P<0.001), and high-sensitivity C-reactive protein (hsCRP) (r=0.701, P<0.001). In multiple regression analysis after controlling for confounders, increased hsCRP levels (β=7.430, P<0.001) and T2DM with hypertriglyceridemia (β=11.496, P=0.002) were independently related to high serum RANTES levels. After 8 weeks of fenofibrate treatment, serum RANTES significantly decreased in group A compared with baseline (52.75±17.41 vs. 59.04±16.74 ng/ml, P=0.018). Conclusions Fenofibrate decreased serum RANTES levels in T2DM patients with hypertriglyceridemia, indicating that PPAR-α agonists may play an important role in inhibiting inflammatory responses.
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Affiliation(s)
- Xiaomeng Feng
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland)
| | - Xia Gao
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland)
| | - Yumei Jia
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland)
| | - Heng Zhang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland)
| | - Yuan Xu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland)
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (mainland)
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