PROJECT SUMMARY/ABSTRACT
Cardiovascular disease is the leading cause of death in the world. Changes in cardiac metabolic
substrate utilization underlie, and may play a causative role in, the development of heart failure. A
critical point of regulation in the ability of the heart to fully oxidize glucose is that of the pyruvate
dehydrogenase (PDH) complex that, in the heart, is negatively regulated by phosphorylation mediated
by two PDH kinases (PDK2 and PDK4). PDKs are differentially regulated in response to physiological
stimuli (e.g., exercise) and pathological stimuli (e.g., heart failure). Therefore, they represent likely
candidates for therapeutic intervention. However, early attempts to regulate the PDKs have not
fully tested the individual isoforms. A long-term goal of our laboratory is to understand the role of
these different isoforms in the progression of heart failure. Our preliminary data using germline knockout
mice for either of these isoforms in a pressure-overload induced model of heart failure, provides
compelling data for a protective role for loss of Pdk2, and an exacerbated role for loss of Pdk4.
Furthermore, our initial characterization identified several PDK isoform specific molecular
differences, including higher protein acetylation in Pdk2-/- hearts and a higher mortality in
Pdk4-/- mice. We also provide evidence to support a mechanism by which the differential acetylation is
targeted to the nucleus and may play a role in the histone code, linking it to epigenetic regulation
of gene expression. A critical barrier in determining the molecular mechanisms of these PDK isoforms
has been the ability to examine each individually. To overcome this barrier, we have generated
inducible cardiomyocyte specific knockouts to test the tissue-specific roles of these kinases in adult
hearts. The objective of the current proposal is to test the hypothesis that loss of PDK2, but not
PDK4, is cardioprotective through differential epigenetic (histone protein acetylation) and
transcriptional regulation in response to pressure-overload induced heart failure. We have developed
two novel mouse models to test this hypothesis. In this proposal we will: determine the role of each
PDK isoform in heart failure progression (Aim 1) and identify molecular mechanisms of these
differences (Aim 2). Collectively, the completion of these studies will provide fundamental insights into
the mechanistic basis for individual PDK isoforms in the regulation of cardiac gene expression
contributing to the development of heart failure.
