Novel Nuclear GRK5 Activity in the heart: Good or Bad?

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Heart failure (HF) is a major health problem and the pathological endpoint after cardiac injury that is characterized by a loss of cardiac pump function and inotropic reserve. Often, myocardial hypertrophy occurs after cardiac stress or injury preceding and contributing to the onset of HF. This pathological process may also involve a loss of repair or regeneration mechanisms, which combined with the cardiac injury results in pump failure. G protein-coupled receptors (GPCRs) play a critical role in the regulation of heart function including being key players in the cardiac hypertrophic process. GPCRs undergo regulation triggered by phosphorylation and subsequent desensitization via a family of kinases known as GPCR kinases (GRKs). Desensitization leads to the loss of downstream signaling. It is becoming increasingly clear that GRKs can play a critical role in modulating myocardial signaling and function. The actions of GRKs appear to become especially important during conditions of compromised heart function such as in hypertrophy and failure. The most abundant GRK in the heart is GRK2 (or PARK1) and GRKS is a second GRK highly expressed in the heart. Both GRK2 and GRKS have been shown to be up-regulated in human HF and also in animal models of cardiac hypertrophy and HF. Through the use of transgenic mice, we have shown that mice overexpressing GRK2 in the heart have a different phenotype from those overexpressing GRKS. Over the last decade, our research has focused on GRK2 and we have shown that inhibition of its activity in the failing heart is beneficial. Novel data from our lab has now shown that GRKS is also a potential target in the hypertrophied and failing heart and its role in the heart should be explored in more depth. Specifically, we have found that unlike cardiac GRK2 overexpressors and wild-type control mice, transgenic mice with increased cardiac levels of GRKS do not tolerate chronic pressure overload exerted by transverse aortic constriction (TAG) as there is rapid decompensation, HF and early death. Interestingly, GRKS, but not GRK2, has been shown to reside in the nucleus of cells and can bind to DMA suggesting that it may play a role in the regulation of gene transcription. Since gene transcriptional events are tightly linked to myocardial hypertrophy, novel nuclear effects of GRKS may be involved in the abnormal hypertrophic response seen in GRKS transgenic mice. Indeed, we have preliminary evidence that GRKS can interact with and phosphorylate Class II histone deacetylases (HDACs), which are major transcriptional repressers known to play a critical role in cardiac hypertrophy. In this project, we plan to test our Central Hypothesis, which is that GRKS plays a novel role in cardiomyocyte signaling and function, including a critical role in the hearts response to injury, due to its localization and activity in the nucleus. Our associated Specific Aims to test this hypothesis are: [1] To determine the in vivo requirement of myocardial GRKS and its activity in the heart's response to cardiac injury; [2] To characterize transgenic mice with inducible myocyte-targeted expression of GRKS mutants that are either kept out of the nucleus (GRK5ANLS) or kept in the nucleus (GRK5ANES) and to determine the role of nuclear vs. non-nuclear GRKS function in cardiac hypertrophy and HF; and [3] To determine the mechanistic role of myocyte GRKS nuclear localization, including its potential regulation of HDAC function and cardiac gene transcription using in vitro cellular model systems and applying knowledge to our above-described mouse models. These studies will take advantage of the models and expertise present within our PPG group to learn more about the role of GRKS in compromised myocardium and whether it is indeed a potential new molecule to target in pursuit of novel therapeutic strategies for treating HF. Moreover, through interactions within this PPG group we have the opportunity to study whether nuclear GRKS activity may be involved in the repair processes.