Project 3: The impact of estrogen receptor alpha on cardiomyocellular metabolism and health ABSTRACT Inactivating mutations and reductions in ESR1 (encodes ERα) are associated with cardiometabolic disease risk in women and men. Moreover, the menopausal transition drives reduction of cardiometabolic health and increased heart failure incidence. However, the causal mechanisms underlying heart failure risk in women during this life phase, and the specific cell types impacted by impairment in estrogen action are inadequately defined. Since aspects of cardiometabolic decline including insulin resistance, obesity, and cardiac dysfunction are recapitulated in ERα null mice, our laboratory has subsequently performed a tissue dissection approach to understand the cell-specific impact of ERα action on metabolism and tissue function. In this proposal we focused specifically on the role of ERα on cardiac function. A primary limitation regarding previous reports of estradiol action in cardiac tissue is the lack of specificity in the manipulation of ERα in cardiomyocytes in vivo. To overcome this limitation, we are the first laboratory to generate mice with a conditional cardiomyocellular-specific knockdown (hERαKD) or overexpression (hERαOE) of Esr1. In Aim 1 of this proposal we will determine the impact of hERαKD on mitochondrial metabolism, cardiac tissue integrity, and heart function. We hypothesize that cardiomyocellular knockdown of Esr1 disrupts mitochondrial metabolism contributing to pathogenic shifts in substrate metabolism, inflammation, fibrosis, and susceptibility to the damaging effects of cardiotoxic agents (e.g. Doxorubicin). In Aim 2 we will determine the impact of conditional cardiomyocellular-specific overexpression of Esr1, hERαOE, on mitochondrial metabolism, cardiac tissue integrity, and protection against high fat diet feeding and cardiotoxic agents. Importantly, phenotypic outcomes in these mouse models, integrated with findings in human subjects, will allow us to ascertain the ERα-regulated transcriptome in heart and establish mechanisms of ERα control over novel target genes. The overarching goal of our work is to determine the impact of impaired estrogen receptor action in the pathobiology of heart failure and identify targets of therapeutic opportunity to protect women against cardiometabolic disease.