Genetic drivers of cardiac remodeling in health and disease in female mice

SWACSM Abstract Genetic drivers of cardiac remodeling in health and disease in female mice Alexander R. Strumwasser1, Timothy M. Moore1, Zhenqi Zhou1, Lorraine P. Turcotte2, Aldons J. Lusis1, Andrea L. Hevener1 1Department of Medicine, University of California, Los Angeles 2Department of Biological Sciences, University of Southern California Hevener Laboratory; Department of Medicine; University of California Los Angeles Laboratory Category: Masters Advisor / Mentor: Hevener, Andrea L. ahevener@mednet.ula.edu ABSTRACT PURPOSE: Sex differences in cardiac metabolism and cardiometabolic disease susceptibility are well documented. However, the mechanisms underlying sexual dimorphism and the role estrogens play in cardiac physiology aren’t well understood, especially in aging women when cardiometabolic disease susceptibility is heightened. The purpose of the current study was to determine key genetic drivers of healthy vs. pathogenic cardiac remodeling and determine the impact of estrogen action on cardiomyocellular function. METHODS: The UCLA Exercise Hybrid Mouse Diversity Panel (ExcHMDP), comprised of ~100 strains of inbred mice, was leveraged to interrogate genetic drivers of cardiac remodeling in response to exercise training. Female mice from the ExcHMDP remained sedentary (SED) or preformed volitional exercise (TRN) by in cage wheel running (30d). Heart samples (4 SED and 4 TRN mice per strain) harvested following a 6h fast, 30h after the last bout of exercise, were subjected to RNA sequencing. A similar analysis was performed on hearts from 91 strains of female mice treated with the cardiac remodeling drug isoproterenol (ISO). Estrogen action related to cardiac remodeling was studied in female mice with a conditional cardiac-specific deletion of estrogen receptor alpha (encoded by Esr1). Integrated informatic assessment of these transcriptomic data sets identified pathways driving healthy versus pathogenic cardiac remodeling. RESULTS: Heart weight was increased following exercise training in 85 of 100 strains studied. Cardiac enrichment analysis of differentially expressed transcripts and candidate gene identification analyses revealed 5 potential regulatory genes associated with healthy cardiac remodeling in response to exercise training. We contrasted these findings with the genetic architecture of two mouse models of cardiac hypertrophy-associated heart failure, the ISO-HMDP and cardiac-specific Esr1 knockout. Mitochondrial function and calcium homeostasis emerged as key pathways of regulation related to cardiac hypertrophy. CONCLUSION: Our studies provide important insight into the genetic architecture and key genetic drivers of cardiac remodeling in females. The goal of our research is to identify cardiac-specific transcripts and pathways that can be targeted therapeutically to preserve cardiac function during aging in women