A role for PPARα in sex differences in cardiac hypertrophy

Abstract

Heart failure remains a leading cause of death worldwide and treatment is complicated by sex differences in the development of this disease. While sex differences in cardiac hypertrophy are well documented, the mechanisms involved are poorly understood. The purpose of this study is to better understand the mechanisms that contribute to sex differences in cardiac hypertrophy. Male and female mice were treated with vehicle or Angiotensin II (AngII; 1.5 mg•kg-1•day-1) to induce cardiac hypertrophy and a systems biology analysis was performed on RNAseq data to identify pathways central to sex differences in cardiac hypertrophy. Cardiac hypertrophy was observed after 2 weeks of AngII and sex differences became apparent after 3 weeks. After 3 weeks of treatment ejection fraction (EF) in females was not different from control values (54% vs 56%). In males, however, EF dropped from 55% to 37%, which was significantly lower than EF in females after 3 weeks of treatment. RNA sequencing was performed on hearts and sex differences in mRNA expression at baseline and following hypertrophy were observed along with differences between baseline and hypertrophy within a sex. Sex differences in mRNA were substantial at baseline and reduced somewhat with hypertrophy, as the hypertrophic differences tended to overwhelm the sex differences. We selected genes that were significant for the sex-disease interaction, and mapped them to the protein-protein interaction network constructed using STRING data. This identified a network centered on PPARα. To examine the role of PPARα in sex differences in cardiac hypertrophy, we treated male and female mice with a PPARα inhibitor (GW6471; (4 mg•kg-1•day-1)) along with vehicle or AngII. The inhibitor blunted the development of hypertrophy in male hearts (+5% AngII+GW6471 vs +20% AngII), blocking sex differences in cardiac hypertrophy. These results suggest that PPARα contributes to sex differences in cardiac hypertrophy.