Targeting the ubiquitin proteasome system in diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy, characterized by impaired contractile function in the absence of coronary artery disease and hypertension [ [1] Severson D.L. Diabetic cardiomyopathy: recent evidence from mouse models of type 1 and type 2 diabetes. Can. J. Physiol. Pharmacol. 2004; 82: 813-823 Crossref PubMed Scopus (94) Google Scholar ], often culminates in heart failure – one of the leading causes of death and disability worldwide [ [2] Circulation. 1999; 100: 1132-1133 Crossref PubMed Scopus (237) Google Scholar ]. Although the molecular mechanisms behind the pathophysiology of diabetic cardiomyopathy are still not fully understood, its progression to heart failure has been associated with mitochondrial dysfunction, increased oxidative stress and impaired calcium handling [ [3] Boudina S. Abel E.D. Diabetic cardiomyopathy revisited. Circulation. 2007; 115: 3213-3223 Crossref PubMed Scopus (1258) Google Scholar ]. It is also assumed that such maladaptations disrupt the cardiac protein homeostasis leading to the accumulation of damaged proteins, which intensifies the cardiac dysfunction [ [4] Toth A. Nickson P. Mandl A. Bannister M.L. Toth K. Erhardt P. Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. Cardiovasc. Hematol. Disord. Drug Targets. 2007; 7: 205-218 Crossref PubMed Scopus (115) Google Scholar ]. In fact, several research groups, including our own, have shown that accumulation of damaged proteins is a common feature of failing hearts from different etiologies, such as diabetes [ 5 Bozi L.H. Jannig P.R. Rolim N. Voltarelli V.A. Dourado P.M. Wisloff U. Brum P.C. Aerobic exercise training rescues cardiac protein quality control and blunts endoplasmic reticulum stress in heart failure rats. J. Cell. Mol. Med. 2016; 20: 2208-2212 Crossref PubMed Scopus (35) Google Scholar , 6 Campos J.C. Queliconi B.B. Dourado P.M. Cunha T.F. Zambelli V.O. Bechara L.R. Kowaltowski A.J. Brum P.C. Mochly-Rosen D. Ferreira J.C. Exercise training restores cardiac protein quality control in heart failure. PLoS One. 2012; 7e52764 Crossref PubMed Scopus (58) Google Scholar , 7 Ferreira J.C. Boer B.N. Grinberg M. Brum P.C. Mochly-Rosen D. Protein quality control disruption by PKCbetaII in heart failure; rescue by the selective PKCbetaII inhibitor, betaIIV5-3. PLoS One. 2012; 7: e33175 Crossref PubMed Scopus (38) Google Scholar , 8 Powell S.R. Samuel S.M. Wang P. Divald A. Thirunavukkarasu M. Koneru S. Wang X. Maulik N. Upregulation of myocardial 11S-activated proteasome in experimental hyperglycemia. J. Mol. Cell. Cardiol. 2008; 44: 618-621 Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar , 9 Gomes K.M. Bechara L.R. Lima V.M. Ribeiro M.A. Campos J.C. Dourado P.M. Kowaltowski A.J. Mochly-Rosen D. Ferreira J.C. Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1. Int. J. Cardiol. 2015; 179: 129-138 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar ].