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Knockdown of estrogen-related receptor α inhibits valve interstitial cell calcification in vitro by regulating heme oxygenase 1
- Source :
- FASEB journal : official publication of the Federation of American Societies for Experimental BiologyREFERENCES. 35(2)
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
HMOX1
Transfection
Biochemistry
Small hairpin RNA
03 medical and health sciences
Estrogen-related receptor
0302 clinical medicine
Downregulation and upregulation
Osteogenesis
Genetics
medicine
Humans
Receptor
Vascular Calcification
Molecular Biology
Aged
Gene knockdown
Chemistry
Calcinosis
Cell Differentiation
Aortic Valve Stenosis
Middle Aged
medicine.disease
Cell biology
Up-Regulation
Heme oxygenase
030104 developmental biology
HEK293 Cells
Receptors, Estrogen
Aortic Valve
Gene Knockdown Techniques
Female
030217 neurology & neurosurgery
Heme Oxygenase-1
Biotechnology
Calcification
Subjects
Details
- ISSN :
- 15306860
- Volume :
- 35
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental BiologyREFERENCES
- Accession number :
- edsair.doi.dedup.....b828f1abbdca6715d4e414a7dc79329d