Cardiac Pathophysiology of Proteasome Phosphoregulation

University Of South Dakota, Vermillion SD

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Abstract

Ischemic heart disease (IHD), including acute and chronic myocardial ischemia, heart attack or acute myocardial infarction (AMI), chronic MI, and other chronic coronary disease, is the most common cause of heart failure (HF) in the US, afflicting the life of millions of Americans. Despite recent advances in the intervention of IHD, the morbidity and mortality of IHD is still high; thus, a better understanding of the molecular mechanisms by which IHD progresses to HF will facilitate the search for new measures to prevent or more effectively delay the progression of IHD to HF. Targeted degradation of most cellular proteins, normal or misfolded, is primarily performed by the ubiquitin-proteasome system (UPS) where the proteasome is a molecular machine to degrade proteins purposely tagged with a chain of ubiquitin. Proteasome malfunction and resultant accumulation of the abnormal or garbage proteins in heart muscle cells are implicated in the progression from IHD to HF; thus, improving cardiac proteasome functioning to expedite the removal of garbage proteins from heart muscle cells after heart attack is conceivably an attractive therapeutic strategy. However, deployment of such a strategy is hindered currently by the lack of pharmacological means. To this end, understanding of how proteasome function is regulated or dysregulated in IHD and what role the (dys)regulation plays in IHD are crucial. The long-term goal of this project is to exploit proteasome regulation for developing new therapeutic strategies. This proposal aims to determine the role of the emerging phosphoregulation of the proteasome by protein kinase A (PKA) in AMI, ischemia/reperfusion injury (IRI), and post-MI maladaptive cardiac remodeling and HF progression. In the last cycle, we have established first in animals that the proteasome subunit RPN6/PSMD11 can be specifically phosphorylated at Ser14 by PKA, resulting in marked increases in proteasome proteolytic function, taking advantage of our newly created gene- edited mice where the phosphorylation of Rpn6 at Ser14 (pS14-Rpn6) is genetically blocked or mimicked. We have now detected remarkable alterations in pS14-RPN6 and total RPN6 proteins in explanted failing human hearts and mouse MI models and striking mitigation of AMI progression by genetic intervention of pS14-RPN6 in mice. Hence, we propose to use genetic approaches to unequivocally establish the mechanistic role of these alterations in AMI, IRI, and chronic post-MI remodeling and HF. This will advance our understanding of IHD pathophysiology and provide genetic demonstration that targeted activation of the proteasome via, for example, compartmental stimulation of PKA could be a new treatment strategy for IHD.