A role for PPAR alpha in regulating sex differences in cardiac hypertrophy

Authors

• N Fillmore
• J Harrington
• S Gao
• Y Yang
• X Zhang
• P Liu
• A Stoehr
• Y Chen
• D Springer
• J Zhu
• X Wang
• E Murphy

Abstract

Heart failure remains a leading cause of death worldwide and treatment is complicated by sex differences in the development of this disease. Males are more likely than females to develop heart failure and cardiac hypertrophy, which contributes to the development of heart failure. 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 (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 Angiotensin II 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% after Angiotensin II treatment vs 56% at baseline). In males, however, EF dropped from 55% at baseline 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 peroxisome proliferator activated receptor (PPAR) alpha. This transcription factor regulates fatty acid oxidation and is known to contribute to the development of cardiac hypertrophy. To examine the role of PPAR alpha in sex differences in cardiac hypertrophy, we treated male and female mice with a PPAR alpha inhibitor (GW6471; (4 mg•kg-1•day-1)) along with vehicle or Angiotensin II for 3 weeks. The PPAR alpha inhibitor blunted the development of hypertrophy in male hearts (5% increase after Angiotensin II +GW6471 treatment vs 20% increase after Angiotensin II treatment), blocking sex differences in cardiac hypertrophy. These results suggest that PPAR alpha contributes to sex differences in the development of cardiac hypertrophy.

Scientific Focus Area: Systems Biology

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