Proteasome biology and therapeutics in cardiac diseases

The ubiquitin proteasome system (UPS) is the major pathway for intracellular protein degradation in most organs, including the heart. UPS controls many fundamental biological processes such as cell cycle, cell division, immune responses, antigen presentation, apoptosis, and cell signaling. The UPS not only degrades substrates but also regulates activity of gene transcription at the post-transcription level. Emerging evidence suggests that impairment of UPS function is sufficient to cause a number of cardiac diseases, including heart failure, cardiomyopathies, hypertrophy, atrophy, ischemia-reperfusion, and atherosclerosis. Alterations in the expression of UPS components, changes in proteasomal peptidase activities and increased ubiquitinated and oxidized proteins have also been detected in diabetic cardiomyopathy (DCM). However, the pathophysiological role of the UPS in DCM has not been examined. Recently, in vitro and in vivo studies have proven highly valuable in assessing effects of various stressors on the UPS and, in some cases, suggesting a causal link between defective protein clearance and disease phenotypes in different cardiac diseases, including DCM. Translation of these findings to human disease can be greatly strengthened by corroboration of discoveries from experimental model systems using human heart tissue from well-defined patient populations. This review will summarize the general role of the UPS in different cardiac diseases, with major focus on DCM, and on recent advances in therapeutic development.