RESEARCH &RELATED Other Project Information 6. Project Summary/Abstract The development of cardiac hypertrophy, the most common precursor to heart failure, is a response of the heart to a wide range of extrinsic stimuli, including hypertension, valvular heart disease, and myocardial infarction. Parallel impairment in fatty acid oxidation and an increase in glucose utilization occur during this process, regulated primarily by the peroxisome proliferator-activated receptor (PPAR) family of transcription factors. The mechanism(s) that regulates this decrease in PPAR transcription factor activity during the development of cardiac hypertrophy is presently unknown. In this proposal, we will first identify the mechanism(s) by which the cardiac specific Muscle Ring Finger-1 (MuRF1) ubiquitinates the PPAR- complex, targeting its proteasome-dependent degradation. These findings will then be confirmed in vivo using our established MuRF1 -/- and MuRF1 cardiac transgenic mouse lines. The role of MuRF1 expression on PPAR-regulated fatty acid and glucose oxidation will then be determined by detecting oxidation metabolites from isolated working heart preparations perfused with radio-labeled fatty acid and glucose. In the second aim of this study, we will determine the signaling pathways which regulate increases in cardiac MuRF1 during cardiac hypertrophy, focusing on NF-B, FOXO, and FAK/MAPK signaling pathways. We will then determine how pressure overload affects MuRF1 and PPAR- activity and localization in cardiac hypertrophy, to elucidate the mechanisms by which MuRF1 interacts and regulates PPAR-, or other components of the PPAR- complex. Lastly, we will elucidate specific mechanisms by which pressure overload induces changes in fatty acid and glucose oxidation by linking the mechanical stretch of cardiomyocytes to increases in MuRF1.
In specific aim three, we will demonstrate the mechanisms by which stretch increases MuRF1 activity by its up-regulation of MuRF1 levels transcriptionally and through the stretch-induced translocation of MuRF1 from the sarcomere into the cytoplasm and nucleus. We will then determine how MuRF1 interacts with nuclear PPAR- during mechanical stretch to regulate fatty acid and glucose oxidation through the mechanisms identified in specific aim #1 (MuRF1 ubiquitination of PPAR- and subsequent degradation by the proteasome) and specific aim #2 (how stretch regulates MuRF1 levels through NF- kB and FOXO signaling pathway). These studies will identify for the first time how mechanical stress from a variety of cardiac pathologies leads to characteristic changes in fatty acid and glucose oxidation through the titin-associated ubiquitin ligase MuRF1. .
RESEARCH &RELATED Other Project Information and Project Narrative. Heart failure is a leading cause of death in the United States, affecting approximately 5.2 million people, with an approximately 60,000 new cases diagnosed each year, costing an estimated $33.2 billion in 2007. While significant changes in metabolism occur during the development of heart failure and its most common precursor cardiac hypertrophy, the underlying mechanisms that regulate these changes are not clearly delineated. Elucidating these novel mechanisms as proposed in this study will help identify targets for the development of therapies for this common disease.
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