Heart failure (HF) is a major public health problem affecting more than 5 million Americans. The total healthcare costs of HF are over $30 billion annually, and are projected to increase as the population ages. Therefore, there is a critical need to develop innovative strategies for prevention and treatment of HF. ?1-adrenergic receptor (?1AR, a seven transmembrane G protein-coupled receptor) signaling is critical to sympathetic regulation of cardiac function, but becomes deleterious in response to chronic catecholamine stimulation during the progression of HF. More recently, it became appreciated that ?1AR signaling involves multiple pathways including a novel cardioprotective signaling (CPS) pathway, in which ?1AR uses ?-arrestin (?-arr) to promote cardiomyocyte (CM) survival in the absence of G protein activation. However, the molecular mechanisms in downstream nuclear processes by which ?-arr-mediated ?1AR signaling confers cardiac protection are not well understood. Based on increasing recognition of microRNAs (miRs) as important regulators of cardiovascular function, we postulated that miR may represent under-appreciated downstream mechanisms regulating the ?-arr- mediated cardioprotection. Our preliminary data show that ?1AR-mediated activation of ?-arr1 enhanced miR processing and expression of several miRs that are known to regulate cell survival and apoptotic pathways. However, the importance of increased ?-arr1-regulated miRs (?1-miRs) to the outcome of cardiac function and tissue injury is unknown and a goal of the current study. The objective of this application is to define the importance of a ?1-miR, miR-150 and two of its CM target genes (pro-apoptotic egr2 and p2x7r) in ?1AR-mediated ?-arrestin1 CPS. The central hypothesis is that ?-arr1- mediated ?1AR regulatory mechanisms confer cardioprotection against myocardial infarction (MI) and chronic catecholamine stimulation via miR-150 processing and altered expression of the two target genes. Guided by extensive preliminary data, our hypothesis will be tested by pursuing three specific aims: 1) Determine if miR-150 modulates cardiac functional responses to coronary ligation and chronic catecholamine stimulation. In vivo loss- and gain-of-function approaches in response to MI and chronic catecholamine treatment will be employed in mice. 2) Determine if increased expression of miR-150 contributes to carvedilol (a ?-arr-biased ?-blocker)-mediated cardioprotection. Both genetic and pharmacological approaches will be used in CM and whole hearts. 3) Elucidate the roles of egr2 and p2x7r, functional CM targets of miR- 150, in HF. Loss- and gain-of-function studies of targets will be performed to show their importance in CM survival and cardiac protection. The proposed work is innovative because the regulation of miR expression by ?-arr signaling has never been studied. We will discover novel regulatory mechanisms of miR processing and function by ?-arrestin1-biased ?1AR signaling pathways and identify potentially important miR-target pairs that are involved in CPS. The proposed re- search is significant because the ability of ?-arr1-biased agonism of ?1AR to regulate cardioprotective miR/pro-apoptotic target pairs holds promise for pharmacological manipulation of HF. Ultimately, such knowledge has the potential to inform the development of novel approaches for the prevention and treatment of a variety of cardiac diseases.
Heart failure is a major cause of morbidity and mortality in the elderly, with expected increase in societal costs due to the aging population. The proposed study is relevant to the public health goal to develop strategies for primary prevention and innovative treatment because the discovery of novel regulatory mechanisms of microRNA processing and function by ?-arrestin1-biased ?1-adrenergic receptor cardioprotective signaling is expected to increase understanding of the pathogenesis of several clinical scenarios of heart failure that are associated with microRNA dysfunction, which will be ultimately amenable for pharmacological manipulation. The proposed research is also relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce the burdens of human heart disease.
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