Abstract P222: Effect Of Western Diet On Pathophysiology And Cardiac Gene Expression Profile In Human AT1 Receptor Over-Expressing Hypertensive Transgenic Mice

Abstract

Human angiotensin II type 1 receptor (hAT1R) gene overexpression may lead to pathophysiological outcomes due to an overdrive of the renin angiotensin system. Our 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, is compounded by the effects of aging and Western diet (WD), which may lead to cardiac complications. However, the underlying mechanisms are not well examined. In this regard, we studied the pathophysiological changes and alterations in transcription profile in the heart of aged Hap-I and Hap-II TG mice following exposure to WD. Aged mice (20-24 months) were maintained on a regular diet or high fat diet with 2% NaCl (WD) for 16 weeks. Following administration of WD, blood pressure increased significantly in Hap-I animals (~15 mmHg), in comparison to Hap-II (~7 mmHg). With respect to Hap-II, aged Hap-I mice show larger heart weight-to-body weight ratio and higher levels of fibrosis on treatment with WD. The TF Activation Profiling (Signosis) after WD treatment shows an increased activation of transcription factors including USF1, CEBP, STAT1, HNF1 in the nuclear extracts from heart of Hap-I TG mice as compared to the Hap-II animals. Competition assay (Promoter-binding TF profiling plate arrays, Signosis) shows stronger binding to the promoter for these TFs binding to the promoter of hAT1R, leading to overexpression of hAT1R in HAP-I TG animals. Transcriptomic analysis from RNA sequencing revealed that WD significantly altered the expression of >500 genes from cardiac tissue of WD treated Hap-I aged mice (compared to control diet treated age-matched mice). Bioinformatics analysis, using Qiagen IPA software, identified major alterations in main canonical pathways involved in cardiac function, inflammation, and oxidative damage. 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.