Cardiovascular disease risk factors induce mesenchymal features and senescence in cardiac endothelial cells

Abstract

Aging, obesity, hypertension and physical inactivity are major risk factors for endothelial dysfunction and cardiovascular disease (CVD). We applied fluorescence-activated cell sorting (FACS), RNA sequencing and bioinformatic methods to investigate the common effects of CVD risk factors on cardiac endothelial cells (ECs). Aging, obesity and pressure overload all upregulated pathways related to TGF-{beta} signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis and cellular senescence, whereas exercise training downregulated most of the same pathways. We identified collagen chaperone SerpinH1/HSP47 to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that SERPINH1/HSP47 in human ECs changed cell morphology and increased mesenchymal gene expression, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs to acquire senescence and mesenchymal features. SERPINH1/HSP47 was identified as a potential therapeutic target in ECs.