天堂网亚洲,天天操天天搞,91视频高清,菠萝蜜视频在线观看入口,美女视频性感美女视频,95丝袜美女视频国产,超高清美女视频图片

ChemicalBook >> journal list >> Cardiovascular Research >>article
Cardiovascular Research

Cardiovascular Research

IF: 10.19
Download PDF

The m6A demethylase ALKBH5 is a novel epigenetic regulator of aortic valve calcification

Published:11 December 2024 DOI: 10.1093/cvr/cvae253
Yueheng Wang, Shengping He, Lan Lan, Hongjiao Yu, Huan Zhao, Yuchen Xie, Guoli Zhong, Liang Yuan, Kun Li, Xiao Hu, Vicky E Macrae, Xiaodong Fu, Guojun Chen, Dongxing Zhu

Abstract

Aims Calcific aortic valve disease (CAVD) is a common heart valve disease with significant clinical consequences. The mechanisms that drive the pathogenesis of CAVD remain to be fully elucidated. N6-methyladenosine (m6A), the most prevalent RNA epigenetic regulator, has recently been implicated in cardiovascular disease, but its role in CAVD has yet to be investigated. In this study, we investigated the potential function of m6A modification in CAVD. Methods and Results Using clinical samples from CAVD patients in combination with human valve interstitial cell (hVIC) calcification model, we screened the expression of m6A modulators and discovered that ALKBH5 alkB homolog 5, RNA demethylase (ALKBH5), a key m6A demethylase, was significantly down-regulated in calcified hVICs and human aortic valves. Consistently, increased m6A levels were seen in calcified hVICs, and treated with 3-deazaadenosine (DAA), an inhibitor of m6A modification, significantly reduced hVIC osteogenic differentiation and calcification. In addition, we showed that silencing of ALKBH5 expression increased global m6A levels, and accelerated hVIC osteogenic differentiation and calcification, whereas overexpression of ALKBH5 resulted in the opposite effect. We demonstrated that ALKBH5 directly modulate m6A levels of TGFBR2 and its mRNA stability, leading to altered TGFBR2 expression and SMAD2 signaling in hVICs. We further showed that inhibition of TGFBR2 or knockdown of SMAD2 attenuated ALKBH5 knockdown-induced hVIC osteogenic differentiation and calcification. The expression of the m6A reader protein YTH N6-methyladenosine RNA binding protein F1 (YTHDF1) was upregulated during the process of hVIC calcification. Intriguingly, we revealed that the ALKBH5 silencing-induced increased hVIC osteogenic differentiation and calcification were abolished after knockdown of YTHDF1. These data suggest a potential role YTHDF1 in aortic valve calcification. Conclusion This study showed that ALKBH5 attenuated aortic valve calcification through the TGFBR2/SMAD2 signaling pathway via direct m6A modification of TGFBR2. .

Substances (1)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Rhamsan gum 96949-21-2 41 suppliers Inquiry

Similar articles

IF:7.1

IL-17A is a key regulator of neuroinflammation and neurodevelopment in cognitive impairment induced by sevoflurane

Free Radical Biology and Medicine Qi Zhang, Yanan Li,etc Published: 22 November 2024
IF:3

MiR-23a-3p targets PTEN as a novel anti-ferroptosis regulator in Fuchs endothelial corneal dystrophy

Experimental eye research Miaomiao Chi, Yaning Zhao,etc Published: 22 November 2024
IF:6.2

344-OR: The MOTS-c/CK2 Pathway Is a Novel Molecular Target for Type 2 Diabetes in East Asians

Diabetes HIROSHI KUMAGAI, SU JEONG KIM,etc Published: 19 July 2024