Knockdown of estrogen-related receptor α inhibits valve interstitial cell calcification in vitro by regulating heme oxygenase 1.
Wangxing HuRongrong WuChenyang GaoFeng LiuZhiru ZengQifeng ZhuJinyong ChenSi ChengKaixiang YuYi QianJing ZhaoShuhan ZhongQingju LiLihan WangXianbao LiuJian'an WangPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2020)
Calcific aortic valve disease (CAVD) is the most common valvular heart disease in adults. The cellular mechanisms of CAVD are still unknown, but accumulating evidence has revealed that osteogenic differentiation of human valve interstitial cells (hVICs) plays an important role in CAVD. Thus, we aimed to investigate the function of estrogen-related receptor α (ERRα) in the osteogenic differentiation of hVICs. We found that the level of ERRα was significantly increased in CAVD samples compared to normal controls. In addition, ERRα was significantly upregulated during hVIC osteogenic differentiation in vitro. Gain- and loss-of-function experiments were performed to identify the function of ERRα in hVIC calcification in vitro. Inhibition of endogenous ERRα attenuated hVIC calcification, whereas overexpression of ERRα in hVICs promoted this process. RNA sequencing results suggested that heme oxygenase-1 (Hmox1) was a downstream target of ERRα, which was further confirmed by western blotting. Additionally, we also found that downregulation of Hmox1 by shHmox1 efficiently reversed the inhibition of calcification induced by ERRα shRNA in hVICs. ChIP-qPCR and luciferase assays indicated that Hmox1 was negatively regulated by ERRα. We found that overexpression of Hmox1 or its substrates significantly inhibited hVIC calcification in vitro. In conclusion, we found that knockdown of ERRα can inhibit hVIC calcification through upregulating Hmox1 and that ERRα and Hmox1 are potential targets for the treatment of CAVD.
Keyphrases
- aortic valve
- chronic kidney disease
- transcatheter aortic valve replacement
- single cell
- cell proliferation
- aortic stenosis
- aortic valve replacement
- mitral valve
- transcatheter aortic valve implantation
- endothelial cells
- high throughput
- stem cells
- mesenchymal stem cells
- coronary artery disease
- risk assessment
- atrial fibrillation
- signaling pathway
- cell therapy
- replacement therapy
- pulmonary hypertension
- smoking cessation
- ejection fraction
- human health