Metabolic Environment Alters the Transcriptomic Landscape of the Aged Heart

Abstract

Eating disorders at older age are coupled with a number of unfavorable health outcomes, including cardiovascular disease; but mechanisms underlying the process remain to be clarified. For this purpose, we studied alterations in gene expression profile of hearts from aged mice following exposure to Western diet. Specifically, we used transgenic mice expressing the haplotype-I (Hap-I: hypertensive genotype) of the human angiotensin receptor type 1 (AT1R) gene because these animals are more prone to develop metabolic syndrome-related disorders. For comparison, mice containing haplotype-II of human AT1R (Hap-II: normotensive genotype) were used. Aged mice (20-24 months of age) were maintained on a regular diet or high fat diet with 2% NaCl (Western diet) for 16 weeks. Blood pressure was monitored by telemetry, whereas cardiac anatomy and gene expression profile were established on heart specimens, using histological and RNA-seq analysis. On regular diet, old Hap-I mice presented higher (~9 mmHg) systolic blood pressure, with respect to aged-matched Hap-II animals. Following administration of Wester diet, 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, increased cell size, and higher levels of fibrosis. Western Diet treatment exacerbated these differences. RNA sequencing data from cardiac tissue of Hap-I aged mice revealed that Western diet 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 Western diet. Overall, these results indicate that Western diet promotes hypertension, hypertrophy, and fibrosis in the heart of aged mice. These alterations are paralleled by perturbation of cardiac transcriptional profile, including upstream gene regulators.