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 in mouse cardiac endothelial cells (ECs). Aging, obesity, and pressure overload all upregulated pathways related to TGF-β signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis, and cellular senescence, whereas exercise training attenuated most of the same pathways. We identified collagen chaperone Serpinh1 (also called as Hsp47) to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that increased SERPINH1 in human ECs induced mesenchymal properties, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs inducing inflammatory, senescence, and mesenchymal features. SERPINH1 was identified as a potential therapeutic target in ECs.
Highlights
According to WHO, cardiovascular diseases (CVDs) account for 10% of the global disease burden and constitute the number 1 cause of death in the western world
To mimic the effect of the most common CVD risk factors, we used adult C57BL/6J wild-type mice in the following experimental groups: aged (18 months) vs. young (2 months) mice, high-fat diet (HFD) induced obesity (14 weeks HFD) vs. lean mice, transverse aortic constriction (TAC) vs. sham-operated mice, and exercise training vs. sedentary mice (Figure 1—figure supplement 1A,B)
The cardiac endothelial cells (ECs) were gated and sorted by fluorescence-activated cell sorting (FACS) (Figure 1—figure supplement 3A), and the isolated ECs were first analyzed by quantitative PCR analysis, which indicated significant enrichment of EC markers Cdh5 and Tie1 in the sorted fraction compared to whole heart or other cardiac mononuclear cells (Figure 1—figure supplement 3B)
Summary
According to WHO, cardiovascular diseases (CVDs) account for 10% of the global disease burden and constitute the number 1 cause of death in the western world. Obesity, high blood pressure, and inactivity all increase the risk of developing cardiovascular diseases, whereas regular exercise has a protective effect It was unclear how these different factors affect endothelial cells. Hemanthakumar et al compared the gene activity of different sets of mice: old vs young, obese vs lean, heart problems vs healthy, and fit vs sedentary All these risk factors – age, weight, inactivity and heart defects – caused the mice’s endothelial cells to activate mechanisms that lead to stress, senescence and fibrosis. We hypothesized that the major CVD risk factors aging, obesity, and pressure overload will induce adverse remodeling of cardiac EC transcriptome (Gimbrone and Garcıa-Cardena, 2016; Ungvari et al, 2018; Brandes, 2014), whereas exercise training would provide beneficial effects (White et al, 1998; Bloor, 2005) Both physiological and pathological stimuli significantly modified the cardiac EC transcriptome. Our results demonstrated that CVD risk factors promoted activation of transforming growth factor-b (TGF-b) signaling, inflammatory response, cellular senescence, and induced mesenchymal gene expression in cardiac EC, whereas exercise training promoted opposite protective effects
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