期刊
BIOMEDICINES
卷 9, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/biomedicines9040427
关键词
valve calcification; valve interstitial cell (VIC); osteogenic differentiation; heme; Nrf2; heme oxygenase-1 (HO-1); ferritin
资金
- Hungarian National Research, Development and Innovation Office (NKFIH) [K131535]
- Hungarian Academy of Sciences, MTA-DE Lendulet Vascular Pathophysiology Research Group [96050]
Calcific aortic valve stenosis (CAVS) is characterized by fibro-calcific remodeling of the aortic valves, and activation of the Nrf2/HO-1 pathway inhibits VIC calcification. This study demonstrates that heme-induced Nrf2/HO-1 expression in VICs inhibits calcification, attributing this effect to the end products generated by HO-1-mediated heme degradation and ferritin.
Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of a variety of antioxidant genes, and plays a protective role in valve calcification. Heme oxygenase-1 (HO-1), an Nrf2-target gene, is upregulated in human calcified aortic valves. Therefore, we investigated the effect of Nrf2/HO-1 axis in VIC calcification. We induced osteogenic differentiation of human VICs with elevated phosphate and calcium-containing osteogenic medium (OM) in the presence of heme. Heme inhibited Ca deposition and OM-induced increase in alkaline phosphatase and osteocalcin (OCN) expression. Heme induced Nrf2 and HO-1 expression in VICs. Heme lost its anti-calcification potential when we blocked transcriptional activity Nrf2 or enzyme activity of HO-1. The heme catabolism products bilirubin, carbon monoxide, and iron, and also ferritin inhibited OM-induced Ca deposition and OCN expression in VICs. This study suggests that heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs. The anti-calcification effect of heme is attributed to the end products of HO-1-catalyzed heme degradation and ferritin.
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