Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Novel Targets of Metformin in Cardioprotection: Beyond the Effects Mediated by AMPK

Author(s): Samir Bolívar*, Laura Noriega, Stefany Ortega, Estefanie Osorio, Wendy Rosales, Xilene Mendoza and Evelyn Mendoza-Torres*

Volume 27, Issue 1, 2021

Published on: 09 May, 2020

Page: [80 - 90] Pages: 11

DOI: 10.2174/1381612826666200509232610

Price: $65

Abstract

Ischemic heart disease is the main cause of death globally. In the heart, the ischemia/reperfusion injury gives rise to a complex cascade of molecular signals, called cardiac remodeling, which generates harmful consequences for the contractile function of the myocardium and consequently heart failure. Metformin is the drug of choice in the treatment of type 2 diabetes mellitus. Clinical data suggest the direct effects of this drug on cardiac metabolism and studies in animal models showed that metformin activates the classical pathway of AMP-activated protein kinase (AMPK), generating cardioprotective effects during cardiac remodeling, hypertrophy and fibrosis. Furthermore, new studies have emerged about other targets of metformin with a potential role in cardioprotection. This state of the art review shows the available scientific evidence of the cardioprotective potential of metformin and its possible effects beyond AMPK. Targeting of autophagy, mitochondrial function and miRNAs are also explored as cardioprotective approaches along with a therapeutic potential. Further advances related to the biological effects of metformin and cardioprotective approaches may provide new therapies to protect the heart and prevent cardiac remodeling and heart failure.

Keywords: Metformin, myocardial ischemia, cardiac remodeling, AMPK, heart failure, fibrosis.

« Previous
[1]
Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab 2014; 20(6): 953-66.
[http://dx.doi.org/10.1016/j.cmet.2014.09.018] [PMID: 25456737]
[2]
Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis 2017; 27(8): 657-69.
[http://dx.doi.org/10.1016/j.numecd.2017.04.009] [PMID: 28709719]
[3]
Mummidi S, Das NA, Carpenter AJ, et al. Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo. J Mol Cell Cardiol 2016; 98: 95-102.
[http://dx.doi.org/10.1016/j.yjmcc.2016.07.006] [PMID: 27423273]
[4]
Ouyang J, Parakhia RA, Ochs RS. Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem 2011; 286(1): 1-11.
[http://dx.doi.org/10.1074/jbc.M110.121806] [PMID: 21059655]
[5]
Park CS, Bang BR, Kwon HS, et al. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem Pharmacol 2012; 84(12): 1660-70.
[http://dx.doi.org/10.1016/j.bcp.2012.09.025] [PMID: 23041647]
[6]
El Messaoudi S, Rongen GA, Riksen NP. Metformin therapy in diabetes: the role of cardioprotection. Curr Atheroscler Rep 2013; 15(4): 314.
[http://dx.doi.org/10.1007/s11883-013-0314-z] [PMID: 23423523]
[7]
Barreto-Torres G, Parodi-Rullán R, Javadov S. The role of PPARα in metformin-induced attenuation of mitochondrial dysfunction in acute cardiac ischemia/reperfusion in rats. Int J Mol Sci 2012; 13(6): 7694-709.
[http://dx.doi.org/10.3390/ijms13067694] [PMID: 22837722]
[8]
Mohsin AA, Chen Q, Quan N, et al. Mitochondrial Complex I Inhibition by Metformin Limits Reperfusion Injury. J Pharmacol Exp Ther 2019; 369(2): 282-90.
[http://dx.doi.org/10.1124/jpet.118.254300] [PMID: 30846619]
[9]
Ramachandran R, Saraswathi M. Postconditioning with metformin attenuates apoptotic events in cardiomyoblasts associated with ischemic reperfusion injury. Cardiovasc Ther 2017; 35(6)e12279
[http://dx.doi.org/10.1111/1755-5922.12279] [PMID: 28643448]
[10]
Gajarsa JJ, Kloner RA. Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities. Heart Fail Rev 2011; 16(1): 13-21.
[http://dx.doi.org/10.1007/s10741-010-9181-7] [PMID: 20623185]
[11]
Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123(1): 92-100.
[http://dx.doi.org/10.1172/JCI62874] [PMID: 23281415]
[12]
Rossello X, Yellon DM. A critical review on the translational journey of cardioprotective therapies! Int J Cardiol 2016; 220: 176-84.
[http://dx.doi.org/10.1016/j.ijcard.2016.06.131] [PMID: 27379920]
[13]
Spath NB, Mills NL, Cruden NL. Novel cardioprotective and regenerative therapies in acute myocardial infarction: a review of recent and ongoing clinical trials. Future Cardiol 2016; 12(6): 655-72.
[http://dx.doi.org/10.2217/fca-2016-0044] [PMID: 27791385]
[14]
Haasenritter J, Stanze D, Widera G, et al. Does the patient with chest pain have a coronary heart disease? Diagnostic value of single symptoms and signs--a meta-analysis. Croat Med J 2012; 53(5): 432-41.
[http://dx.doi.org/10.3325/cmj.2012.53.432] [PMID: 23100205]
[15]
Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357(11): 1121-35.
[http://dx.doi.org/10.1056/NEJMra071667] [PMID: 17855673]
[16]
Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 2015; 65(14): 1454-71.
[http://dx.doi.org/10.1016/j.jacc.2015.02.032] [PMID: 25857912]
[17]
Hausenloy DJ, Tsang A, Mocanu MM, et al. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol - Hear Circ Physiol 2005; 288: 971-6.
[http://dx.doi.org/10.1152/ajpheart.00374.2004]
[18]
Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev 2019; 99(4): 1765-817.
[http://dx.doi.org/10.1152/physrev.00022.2018] [PMID: 31364924]
[19]
D’Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019; 43(6): 582-92.
[http://dx.doi.org/10.1002/cbin.11137] [PMID: 30958602]
[20]
Garcia-Dorado D, Ruiz-Meana M, Inserte J, Rodriguez-Sinovas A, Piper HM. Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res 2012; 94(2): 168-80.
[http://dx.doi.org/10.1093/cvr/cvs116] [PMID: 22499772]
[21]
Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox Biol 2015; 6: 524-51.
[http://dx.doi.org/10.1016/j.redox.2015.08.020] [PMID: 26484802]
[22]
Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res 2002; 53(1): 31-47.
[http://dx.doi.org/10.1016/S0008-6363(01)00434-5] [PMID: 11744011]
[23]
Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 2014; 11(5): 255-65.
[http://dx.doi.org/10.1038/nrcardio.2014.28] [PMID: 24663091]
[24]
Wu MY, Yiang GT, Liao WT, et al. Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cell Physiol Biochem 2018; 46(4): 1650-67.
[http://dx.doi.org/10.1159/000489241] [PMID: 29694958]
[25]
Zweier JL, Talukder MAH. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 2006; 70(2): 181-90.
[http://dx.doi.org/10.1016/j.cardiores.2006.02.025] [PMID: 16580655]
[26]
Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 2016; 1863(12): 2977-92.
[http://dx.doi.org/10.1016/j.bbamcr.2016.09.012] [PMID: 27646922]
[27]
Tian XF, Cui MX, Yang SW, Zhou YJ, Hu DY. Cell death, dysglycemia and myocardial infarction. Biomed Rep 2013; 1(3): 341-6.
[http://dx.doi.org/10.3892/br.2013.67] [PMID: 24648945]
[28]
Ma S, Wang Y, Chen Y, Cao F. The role of the autophagy in myocardial ischemia/reperfusion injury. Biochim Biophys Acta 2015; 1852(2): 271-6.
[http://dx.doi.org/10.1016/j.bbadis.2014.05.010] [PMID: 24859226]
[29]
Dong Y, Undyala VV, Gottlieb RA, Mentzer RM Jr, Przyklenk K. Autophagy: definition, molecular machinery, and potential role in myocardial ischemia-reperfusion injury. J Cardiovasc Pharmacol Ther 2010; 15(3): 220-30.
[http://dx.doi.org/10.1177/1074248410370327] [PMID: 20595626]
[30]
Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007; 100(6): 914-22.
[http://dx.doi.org/10.1161/01.RES.0000261924.76669.36] [PMID: 17332429]
[31]
Valentim L, Laurence KM, Townsend PA, et al. Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury. J Mol Cell Cardiol 2006; 40(6): 846-52.
[http://dx.doi.org/10.1016/j.yjmcc.2006.03.428] [PMID: 16697404]
[32]
Przyklenk K, Undyala VVR, Wider J, Sala-Mercado JA, Gottlieb RA, Mentzer RM Jr. Acute induction of autophagy as a novel strategy for cardioprotection: getting to the heart of the matter. Autophagy 2011; 7(4): 432-3.
[http://dx.doi.org/10.4161/auto.7.4.14395] [PMID: 21187719]
[33]
Przyklenk K, Dong Y, Undyala VV, Whittaker P. Autophagy as a therapeutic target for ischaemia/reperfusion injury? Concepts, controversies, and challenges. Cardiovasc Res 2012; 94(2): 197-205.
[http://dx.doi.org/10.1093/cvr/cvr358] [PMID: 22215722]
[34]
Shinde AV, Frangogiannis NG. Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol 2014; 70: 74-82.
[http://dx.doi.org/10.1016/j.yjmcc.2013.11.015] [PMID: 24321195]
[35]
Dobaczewski M, de Haan JJ, Frangogiannis NG. The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium. J Cardiovasc Transl Res 2012; 5(6): 837-47.
[http://dx.doi.org/10.1007/s12265-012-9406-3] [PMID: 22956156]
[36]
Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 2010; 48(3): 504-11.
[http://dx.doi.org/10.1016/j.yjmcc.2009.07.015] [PMID: 19631653]
[37]
Wu L, Gao L, Zhang D, et al. C1QTNF1 attenuates angiotensin II-induced cardiac hypertrophy via activation of the AMPKa pathway. Free Radic Biol Med 2018; 121: 215-30.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.05.004] [PMID: 29733904]
[38]
Grossman W, Paulus WJ. Myocardial stress and hypertrophy: a complex interface between biophysics and cardiac remodeling. J Clin Invest 2013; 123(9): 3701-3.
[http://dx.doi.org/10.1172/JCI69830] [PMID: 23999445]
[39]
Liu R, Molkentin JD. Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs). J Mol Cell Cardiol 2016; 101: 44-9.
[http://dx.doi.org/10.1016/j.yjmcc.2016.08.018] [PMID: 27575022]
[40]
Sadoshima J, Izumo S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J 1993; 12(4): 1681-92.
[http://dx.doi.org/10.1002/j.1460-2075.1993.tb05813.x] [PMID: 8385610]
[41]
Luckey SW, Walker LA, Smyth T, et al. The role of Akt/GSK-3beta signaling in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 2009; 46(5): 739-47.
[http://dx.doi.org/10.1016/j.yjmcc.2009.02.010] [PMID: 19233194]
[42]
Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 2014; 71(4): 549-74.
[http://dx.doi.org/10.1007/s00018-013-1349-6] [PMID: 23649149]
[43]
Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol Aspects Med 2019; 65: 2-15.
[http://dx.doi.org/10.1016/j.mam.2018.06.003] [PMID: 29958900]
[44]
Frangogiannis NG. The role of transforming growth factor (TGF)-β in the infarcted myocardium. J Thorac Dis 2017; 9(Suppl. 1): S52-63.
[http://dx.doi.org/10.21037/jtd.2016.11.19] [PMID: 28446968]
[45]
Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: The fibroblast awakens. Circ Res 2016; 118(6): 1021-40.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306565] [PMID: 26987915]
[46]
Garcia D, Shaw RJ. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol Cell 2017; 66(6): 789-800.
[http://dx.doi.org/10.1016/j.molcel.2017.05.032] [PMID: 28622524]
[47]
Bairwa SC, Parajuli N, Dyck JRB. The role of AMPK in cardiomyocyte health and survival. Biochim Biophys Acta 2016; 1862(12): 2199-210.
[http://dx.doi.org/10.1016/j.bbadis.2016.07.001] [PMID: 27412473]
[48]
Zaha VG, Young LH. AMP-activated protein kinase regulation and biological actions in the heart. Circ Res 2012; 111(6): 800-14.
[http://dx.doi.org/10.1161/CIRCRESAHA.111.255505] [PMID: 22935535]
[49]
Xu X, Lu Z, Fassett J, et al. Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase α2. Hypertension 2014; 63(4): 723-8.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.02619] [PMID: 24420540]
[50]
Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108(8): 1167-74.
[http://dx.doi.org/10.1172/JCI13505] [PMID: 11602624]
[51]
Elmadhun NY, Sabe AA, Lassaletta AD, Chu LM, Sellke FW. Metformin mitigates apoptosis in ischemic myocardium. J Surg Res 2014; 192(1): 50-8.
[http://dx.doi.org/10.1016/j.jss.2014.05.005] [PMID: 24969550]
[52]
Wang Y, Yang Z, Zheng G, et al. Metformin promotes autophagy in ischemia/reperfusion myocardium via cytoplasmic AMPKα1 and nuclear AMPKα2 pathways. Life Sci 2019; 225: 64-71.
[http://dx.doi.org/10.1016/j.lfs.2019.04.002] [PMID: 30953640]
[53]
Kinsara AJ, Ismail YM. Metformin in heart failure patients. Indian Heart J 2018; 70(1): 175-6.
[http://dx.doi.org/10.1016/j.ihj.2017.05.009] [PMID: 29455774]
[54]
Xiao H, Ma X, Feng W, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res 2010; 87(3): 504-13.
[http://dx.doi.org/10.1093/cvr/cvq066] [PMID: 20200042]
[55]
Yang X, Xu Z, Zhang C, Cai Z, Zhang J. Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells. Biochim Biophys Acta Mol Basis Dis 2017; 1863(8): 1984-90.
[http://dx.doi.org/10.1016/j.bbadis.2016.09.019] [PMID: 27702625]
[56]
Zhai C, Shi W, Feng W, et al. Activation of AMPK prevents monocrotaline-induced pulmonary arterial hypertension by suppression of NF-κB-mediated autophagy activation. Life Sci 2018; 208: 87-95.
[http://dx.doi.org/10.1016/j.lfs.2018.07.018] [PMID: 30009823]
[57]
Cittadini A, Napoli R, Monti MG, et al. Metformin prevents the development of chronic heart failure in the SHHF rat model. Diabetes 2012; 61(4): 944-53.
[http://dx.doi.org/10.2337/db11-1132] [PMID: 22344560]
[58]
Soraya H, Clanachan AS, Rameshrad M, Maleki-Dizaji N, Ghazi-Khansari M, Garjani A. Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Eur J Pharmacol 2014; 737: 77-84.
[http://dx.doi.org/10.1016/j.ejphar.2014.05.003] [PMID: 24842192]
[59]
Li S, Han D, Zhang Y, et al. Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery. Med Sci Monit Basic Res 2016; 22: 27-33.
[http://dx.doi.org/10.12659/MSMBR.897505] [PMID: 26978596]
[60]
Nafisa A, Gray SG, Cao Y, et al. Endothelial function and dysfunction: Impact of metformin. Pharmacol Ther 2018; 192: 150-62.
[http://dx.doi.org/10.1016/j.pharmthera.2018.07.007] [PMID: 30056057]
[61]
Li Y, Chen C, Yao F, et al. AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1. Arch Biochem Biophys 2014; 558: 79-86.
[http://dx.doi.org/10.1016/j.abb.2014.06.023] [PMID: 25009141]
[62]
Cates C, Rousselle T, Wang J, et al. Activated protein C protects against pressure overload-induced hypertrophy through AMPK signaling. Biochem Biophys Res Commun 2018; 495(4): 2584-94.
[http://dx.doi.org/10.1016/j.bbrc.2017.12.125] [PMID: 29287725]
[63]
Burlá AK, Lobato NS, Fortes ZB, Oigman W, Neves MF. Cardiac fibrosis and vascular remodeling are attenuated by metformin in obese rats. Int J Cardiol 2013; 165(3): 483-7.
[http://dx.doi.org/10.1016/j.ijcard.2011.09.012] [PMID: 21945710]
[64]
Soraya H, Rameshrad M, Mokarizadeh A, Garjani A. Metformin attenuates myocardial remodeling and neutrophil recruitment after myocardial infarction in rat. Bioimpacts 2015; 5(1): 3-8.
[http://dx.doi.org/10.15171/bi.2015.02] [PMID: 25901291]
[65]
Daskalopoulos EP, Dufeys C, Bertrand L, Beauloye C, Horman S. AMPK in cardiac fibrosis and repair: Actions beyond metabolic regulation. J Mol Cell Cardiol 2016; 91: 188-200.
[http://dx.doi.org/10.1016/j.yjmcc.2016.01.001] [PMID: 26772531]
[66]
Bai J, Zhang N, Hua Y, et al. Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts. PLoS One 2013; 8(9)e72120
[http://dx.doi.org/10.1371/journal.pone.0072120] [PMID: 24023727]
[67]
Wang XF, Zhang JY, Li L, Zhao XY, Tao HL, Zhang L. Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clin Exp Pharmacol Physiol 2011; 38(2): 94-101.
[http://dx.doi.org/10.1111/j.1440-1681.2010.05470.x] [PMID: 21143620]
[68]
Xavier DO, Amaral LS, Gomes MA, et al. Metformin inhibits inflammatory angiogenesis in a murine sponge model. Biomed Pharmacother 2010; 64(3): 220-5.
[http://dx.doi.org/10.1016/j.biopha.2009.08.004] [PMID: 20053525]
[69]
Fan K, Wu K, Lin L, et al. Metformin mitigates carbon tetrachloride-induced TGF-β1/Smad3 signaling and liver fibrosis in mice. Biomed Pharmacother 2017; 90: 421-6.
[http://dx.doi.org/10.1016/j.biopha.2017.03.079] [PMID: 28390311]
[70]
Jiang S, Li T, Yang Z, et al. AMPK orchestrates an elaborate cascade protecting tissue from fibrosis and aging. Ageing Res Rev 2017; 38: 18-27.
[http://dx.doi.org/10.1016/j.arr.2017.07.001] [PMID: 28709692]
[71]
Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injuryAnnals of the New York Academy of Sciences. New York Academy of Sciences 2005; Vol. 1047: pp. 248-58.
[72]
Detaille D, Guigas B, Chauvin C, et al. Metformin prevents high- glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005; 54(7): 2179-87.
[http://dx.doi.org/10.2337/diabetes.54.7.2179] [PMID: 15983220]
[73]
Bhamra GS, Hausenloy DJ, Davidson SM, et al. Metformin pro- tects the ischemic heart by the Akt-mediated inhibition of mito- chondrial permeability transition pore opening. Basic Res Cardiol 2008; 103(3): 274-84.
[http://dx.doi.org/10.1007/s00395-007-0691-y] [PMID: 18080084]
[74]
Stewart S, Lesnefsky EJ, Chen Q. Reversible blockade of electron transport with amobarbital at the onset of reperfusion attenuates cardiac injury. Transl Res 2009; 153(5): 224-31.
[http://dx.doi.org/10.1016/j.trsl.2009.02.003] [PMID: 19375683]
[75]
Xu A, Szczepanek K, Maceyka MW, et al. Transient complex I inhibition at the onset of reperfusion by extracellular acidification decreases cardiac injury. Am J Physiol Cell Physiol 2014; 306(12): C1142-53.
[http://dx.doi.org/10.1152/ajpcell.00241.2013] [PMID: 24696146]
[76]
Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion In- jury Salvage Kinase (RISK)-pathway. Cardiovasc Res 2004; 61(3): 448-60.
[http://dx.doi.org/10.1016/j.cardiores.2003.09.024] [PMID: 14962476]
[77]
Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome pro- liferator-activated receptor-α in mice. Diabetologia 2011; 54(2): 339-49.
[http://dx.doi.org/10.1007/s00125-010-1937-z] [PMID: 20972533]
[78]
Bai F, Liu Y, Tu T, et al. Metformin regulates lipid metabolism in a canine model of atrial fibrillation through AMPK/PPAR-α/VLCAD pathway. Lipids Health Dis 2019; 18(1): 109.
[http://dx.doi.org/10.1186/s12944-019-1059-7] [PMID: 31077199]
[79]
Schulman D, Latchman DS, Yellon DM. Urocortin protects the heart from reperfusion injury via upregulation of p42/p44 MAPK signaling pathway. Am J Physiol - Hear Circ Physiol 2002; 283: 52-4.
[80]
Rossello X, Yellon DM. The RISK pathway and beyond. Basic Res Cardiol 2017; 113(1): 2.
[http://dx.doi.org/10.1007/s00395-017-0662-x] [PMID: 29143177]
[81]
Choi E, Cha M-J, Hwang K-C. Roles of Calcium Regulating Mi- croRNAs in Cardiac Ischemia-Reperfusion Injury. Cells 2014; 3(3): 899-913.
[http://dx.doi.org/10.3390/cells3030899] [PMID: 25216032]
[82]
Zhang CX, Pan SN, Meng RS, et al. Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase- endothelial nitric oxide synthase pathway in rats. Clin Exp Pharmacol Physiol 2011; 38(1): 55-62.
[http://dx.doi.org/10.1111/j.1440-1681.2010.05461.x] [PMID: 21083698]
[83]
Xu J, Wu W, Zhang L, et al. The role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment: correction with mesenchymal stem cell treatment. Diabetes 2012; 61(11): 2906-12.
[http://dx.doi.org/10.2337/db12-0145] [PMID: 22851573]
[84]
Sastre ME, Prat MO, Checa MA, Carreras RC. Current trends in the treatment of polycystic ovary syndrome with desire for children. Ther Clin Risk Manag 2009; 5(2): 353-60.
[PMID: 19536311]
[85]
Oidor-Chan VH, Hong E, Pérez-Severiano F, et al. Fenofibrate plus Metformin Produces Cardioprotection in a Type 2 Diabetes and Acute Myocardial Infarction Model. PPAR Res 2016; 20168237264
[http://dx.doi.org/10.1155/2016/8237264] [PMID: 27069466]
[86]
Al-Rasheed NM, Al-Rasheed NM, Al-Rabeeah DA, et al. Possible protective mechanisms exerted by metformin or metformin and vi- tamin E in isoproterenol-induced cardiac injury. J Cell Biochem 2018; 119(5): 3903-12.
[http://dx.doi.org/10.1002/jcb.26530] [PMID: 29165830]
[87]
Effects of Vildagliptin/Metformin Combination on Markers of Atherosclerosis, Thrombosis, and Inflammation in Diabetics With Coronary Artery Disease [homepage on the Internet] ClinicalTrials.gov. U.S. National Medicine [cited 2020 Feb 10] https://clinicaltrials.gov/ct2/show/NCT01604213?term=NCT01604 213&draw=2&rank=1" Available from:
[88]
MetfoRmin and Its Effects on Left Ventricular Hypertrophy in Normotensive Patients With Coronary Artery Disease [homepage on the Internet] ClinicalTrials.gov. US National Medicine [cited 2020 Feb 10] https://clinicaltrials.gov/ct2/show/NCT02226510?term=NCT02226 510&draw=2&rank=1 Available from:
[89]
Metformin Reduces Left Ventricular Mass in Patients With Ischemic Heart Disease [homepage on the Internet] ClinicalTrials.gov. US National Medicine [cited 2020 Feb 10] https://clinicaltrials.gov/ct2/show/NCT01879293?term=NCT018799 293&draw=1&rank=1 Available from:
[90]
Metformin to Reduce Heart Failure After Myocardial Infarction [homepage on the Internet] ClinicalTrials.gov. US National Medicine [cited 2020 Feb 10] https://clinicaltrials.gov/ct2/show/NCT01217307?term=NCT012177 307&draw=2&rank=1 Available from:
[91]
The Metformin in Coronary Artery Bypass Graft (CABG). (MetCAB) Trial [homepage on the Internet] ClinicalTrials.gov. U.S. National Medicine [cited 2020 Feb 10] https://clinicaltrials.gov/ct2/show/NCT01438723?term=NCT014388 723&draw=1&rank=1 Available from:

Rights & Permissions Print Cite
Article Metrics
24
1
© 2024 Bentham Science Publishers | Privacy Policy