The role of the proteasome in heart disease

Abstract

Intensive investigations into the pathophysiological significance of the proteasome in the heart did not start until the beginning of the past decade but exciting progresses have been made and are summarized here as two fronts. First, strong evidence continues to emerge to support a novel hypothesis that proteasome functional insufficiency represents a common pathological phenomenon in a large subset of heart disease, compromises protein quality control in heart muscle cells, and thereby acts as a major pathogenic factor promoting the progression of the subset of heart disease to congestive heart failure. This front is represented by the studies on the ubiquitin-proteasome system (UPS) in cardiac proteinopathy, which have taken advantage of a transgenic mouse model expressing a fluorescence reporter for UPS proteolytic function. Second, pharmacological inhibition of the proteasome has been explored experimentally as a potential therapeutic strategy to intervene some forms of heart disease, such as pressure overload cardiac hypertrophy, viral myocarditis, and myocardial ischemic injury. Not only between the two fronts but also within each one, a multitude of inconsistency and controversy remain to be explained and clarified. At present, the controversy perhaps reflects the sophistication of cardiac proteasomes in terms of the composition, assembly, and regulation, as well as the intricacy and diversity of heart disease in terms of its etiology and pathogenesis. A definitive role of altered proteasome function in the development of various forms of heart disease remains to be established.

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

“…The results are in concordance with a number of studies on LVH remodeling in both mice and humans (33,49,63), in aging hearts (8), and ischemia-reperfusion injury (21,60) but is in discordance with other studies (5,12,20,32,45,46). The explanations for the varying responses in the LV have been debated (31,43) and may be related to differences in the animal models or in techniques used in assessing proteasome activity. In accordance with other models of cardiac stress, the changes among the proteasome components following PAC indicate differential regulation of specific proteasomal enzyme activities in cardiac remodeling offering opportunities for targeted therapeutic interventions (23,30,33).…”

“…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.…”

“…However, studies have been contradictory, showing either increased or decreased proteasomal enzyme activity in the afterload stressed LV (31,43). Other models have demonstrated both cardioprotective (9,21,25,59) and cardiotoxic (12,20,27,32,45,46) roles of the UPS via regulation of apoptosis, NF-B signaling, and oxidative stress.…”

Review of cardiac protein quality control and major degradation pathways

“…Although, proteasome inhibition is clinically employed to treat certain types of cancer, it has shown promising efficacy but severe adversary effects on the heart have also been reported (Li and Wang, 2011). Therefore, it is important to have a better understanding of how cardiomyocytes and the heart respond to proteasome Inhibition/malfunction.…”

“…But recent studies suggest that macroautophagy (commonly known as autophagy) may also play a role in PQC-associated proteolysis, especially when UPS function becomes inadequate (Su and Wang, 2010). The development of a range of heart diseases, including bona fide cardiac proteinopathies and various forms of cardiac dysfunction has been linked to proteasome functional insufficiency (PFI) (Su and Wang, 2010;Li and Wang, 2011).…”