Abstract
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.
Highlights
Because Heme oxygenase-1 (HO-1) has been found to be upregulated in human calcified aortic valves [32], we investigated the effect of the Nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathway activation on P- and Ca-induced osteogenic differentiation and extracellular matrix (ECM) calcification of valvular interstitial cells (VICs)
Therewe whether the heme-mediated upregulation of Nrf2 waswas accompanied by fore,investigated we investigated whether the heme-mediated upregulation of Nrf2 accompanied increased expression of HO-1
The data reported in the present study suggest that the heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Calcific aortic valve stenosis (CAVS) is a heart disease characterized by a progressive fibro-calcific remodeling and thickening of the aortic valves eventually leading to severe heart outflow tract obstruction [1]. CAVS is the second-most frequent cardiovascular disease, with a prevalence of 0.4% in the general population. It is considered an aging disease, as the prevalence of severe CAVS increases to 1.7% in the population over 65 years old [1]
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