Proteasome functional insufficiency in cardiac pathogenesis

Abstract

The ubiquitin-proteasome system (UPS) is responsible for the degradation of most cellular proteins. Alterations in cardiac UPS, including changes in the degradation of regulatory proteins and proteasome functional insufficiency, are observed in many forms of heart disease and have been shown to play an important role in cardiac pathogenesis. In the past several years, remarkable progress in understanding the mechanisms that regulate UPS-mediated protein degradation has been achieved. A transgenic mouse model of benign enhancement of cardiac proteasome proteolytic function has been created. This has led to the first demonstration of the necessity of proteasome functional insufficiency in the genesis of important pathological processes. Cardiomyocyte-restricted enhancement of proteasome proteolytic function by overexpression of proteasome activator 28α protects against cardiac proteinopathy and myocardial ischemia-reperfusion injury. Additionally, exciting advances have recently been achieved in the search for a pharmacological agent to activate the proteasome. These breakthroughs are expected to serve as an impetus to further investigation into the involvement of UPS dysfunction in molecular pathogenesis and to the development of new therapeutic strategies for combating heart disease. An interplay between the UPS and macroautophagy is increasingly suggested in noncardiac systems but is not well understood in the cardiac system. Further investigations into the interplay are expected to provide a more comprehensive picture of cardiac protein quality control and degradation.

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

“…The specificity of substrates for proteasomal degradation is primarily conferred by the E3 ubiquitin ligases. MuRF1 has been reported to be upregulated in hypertrophic and failing hearts (71). We found that the Smurf1 ubiquitin ligase expression is upregulated in PAC, the first report identifying a role of Smurf1 in cardiac hypertrophy.…”

“…UPS activity has been shown to be decreased (19,49) in human LVF; however, in rodent models of LVH and LVF, studies have shown either increased or decreased UPS activity (31,43,71). Thus the role of the UPS in LVH/LVF is still unclear.…”

“…Three peptidase activities, chymotrypsin-like, trypsin-like, and caspase-like activities, have been assigned to the ␤ 5 , ␤ 2 , and ␤ 1 subunits, respectively, of the 20S core proteasomal complex, capped by 19S regulatory and/or 11S activator complexes. The UPS also interacts with lysosomal (autophagy dependent or independent) and other protease-specific pathways within the cardiomyocyte (17,71).…”

The ubiquitin proteasome system in human cardiomyopathies and heart failure

“…UPS function has been interrogated in a variety of in vitro and animal models and comprehensively reviewed elsewhere (40,53,66,67,78,85,91,94,100,103). Published studies most relevant for comparison to human cardiomyopathies are the 1) mouse models of desmin-related cardiomyopathies (DRCs), 2) cardiac hypertrophy models (i.e., thoracic aortic banding, isoproterenol induced), and 3) HCM-associated myosin binding protein C (MYBPC3) mutant knock in mice.…”

Protein kinetic signatures of the remodeling heart following isoproterenol stimulation

“…The turnover cycle becomes perturbed during cardiac injury and heart failure by factors including hypertrophic signaling (4), calcium regulation (5), and proteolytic stress (6,7), whereas increased oxidative stress compounds the reduced protein degradation capacity of the failing heart (8). Altogether, these perturbations of protein degradation and synthesis instigate a remodeling of the cardiac proteome that is believed to parallel, at the molecular level, the progressive deterioration of cardiac structure and functions (4,(8)(9)(10)(11). Hence, identifying how pathological proteome remodeling gradually manifests over time is critical to advancing our knowledge of heart diseases.…”