Abstract P479: Pathogenesis And Altered Cardiac Transcriptomic Landscape In Western Diet Treated Aged Mice Overexpressing Human Angiotensin Type 1 Receptor

Abstract

Overexpression of human angiotensin II type 1 receptor (hAT1R) may lead to pathophysiological outcomes due to overactivation of the renin angiotensin system. We have shown that transgenic (TG) mice containing Hap-I (hypertensive genotype) of human AT1R gene are more prone to develop metabolic syndrome (MetS) as compared to TG mice with Hap-II (normotensive genotype). The increased risk of MetS, especially in hypertension, compounded by the effects of aging and Western diet (WD), which may lead to cardiac complications. However, the underlying mechanisms are not well examined. For this purpose, we studied the pathophysiological changes and gene expression profile alterations in the heart of aged Hap-I and Hap-II TG mice following exposure to WD. Aged mice (20-24 months of age) were maintained on a regular diet or high fat diet with 2% NaCl (WD) for 16 weeks. On regular diet, aged Hap-I mice presented higher (~9 mmHg) systolic blood pressure with respect to age-matched Hap-II animals. Following administration of WD, blood pressure increased in both groups of mice, but to a larger extent in Hap-I animals (~15 mmHg), in comparison to Hap-II (~7 mmHg). With respect to Hap-II, aged Hap-I mice on regular diet tended to have larger heart weight-to-body weight ratio and higher levels of fibrosis. Western Diet treatment exacerbated these differences. RNA sequencing data from cardiac tissue of WD treated Hap-I aged mice (compared to control diet treated age-matched mice) revealed that WD significantly altered the expression of >500 genes (p-adj. <0.05). Bioinformatics analysis, using Qiagen IPA software, identified major alterations in main canonical pathways involved in cardiac function, inflammation, and oxidative damage. Top hits in the disease and biological function category included arrhythmia, chamber enlargement, and cell death. Importantly, IRF3, IRF7, IFNG and STAT1 were among the top upstream regulators significantly affected by WD. Overall, these results indicate that Western diet promotes hypertension, hypertrophy, and fibrosis in the heart of aged mice. Results from these studies will assist in the identification of novel molecules and mechanisms involved in hypertension and associated cardiac pathophysiology.