Cardiovascular disease is the leading cause of death in the United States. One factor that increases the incidence of heart failure is aging. Several clinical reports have highlighted how physiological processes that regulate proper functioning of cardiac tissue decline as individual ages. One of these processes is regulated by the actions of PHLPP, a serine/threonine phosphatase that has been shown to regulate cell growth and survival through dephosphorylation of several members of the AGC kinase family including Akt. The levels of PHLPP expression have been associated with several diseases that are correlated with aging including cancer, diabetes and cardiovascular disease. With age, neurohormonal signaling like Akt becomes chronically activated. The role of PHLPP2 in cardiovascular pathology and the role of aging are unknown. Studies in this proposal will examine the mechanism of PHLPP2 protein expression with age and its effect on post- translational and epigenetic modifications. We hypothesize that PHLPP2 levels are altered with age and regulate epigenetic changes to influence transcriptional networks important for cellular homeostasis. We have demonstrated for the first time a novel interaction between PHLPP2 and the G-protein coupled receptor kinase 5 (GRK5) to regulate phenylephrine induced cardiomyocyte growth. Next generation sequencing uncovered transcriptional networks altered in the heart by PHLPP2 removal that regulates growth factor receptor signaling and metabolic processes. Mitochondria are critical for the energy required by the heart, and therefore, play an important role in survival and function of the cardiomyocytes. In the first aim using young and aged wild-type and PHLPP2 KO mice we will determine the mechanism of the regulation of PHLPP2 isoform expression in the heart with age and its effect on mitochondrial function basally and following ischemic injury.
Aim two will investigate the effect of posttranslational modification of GRK5 by PHLPP2 on its ability to regulate cardiac hypertrophy signaling. Lastly, in aim three we will define the epigenetic mechanisms required for PHLPP2 mediated regulation of transcriptional changes in vitro and in vivo that is important for cardiac homeostasis. Using both in vitro and in vivo systems we aim to test the proposed hypothesis and significantly impact our current understanding of cardiac outcome associated with epigenetic modifications. The long-term goal of this proposal is determine novel targets of PHLPP2 and uncover its mechanism of action in regulating cardiac growth and metabolic signaling with aging.
/RELEVANCE: Cardiovascular disease and development of heart failure are amongst the primary causes of death in the United States and worldwide. We have found that the phosphatase PHLPP2 increases with age in the heart and negatively regulates cardiac growth. Here we seek to further understand the regulation of PHLPP2 expression with age and cardiac injury and its regulation of cardiac homeostasis to determine the potential for PHLPP2 as a target for therapeutic strategies to improve cardiac function.
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