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

eLife

Eero Mervaala¹  Mikko I Mäyränpää²  Karthik Amudhala Hemanthakumar³  Riikka Kivelä³  Andrey Anisimov⁴  Shentong Fang⁴ 

[1] Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland;Pathology, Helsinki University and Helsinki University Hospital, Helsinki, Finland;Wihuri Research Institute, Helsinki, Finland;Stem cells and Metabolism Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland;Wihuri Research Institute, Helsinki, Finland;Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland;

关键词: aging;    obesity;    exercise;    heart;    endothelium;    Human;    Mouse;   

DOI  :  10.7554/eLife.62678

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY