AVCAPIR: A Novel Procalcific PIWI-Interacting RNA in Calcific Aortic Valve Disease

作者：Dong Han, Tingwen Zhou, Lifu Li, Yan Ma, Shiqi Chen, Chunguang Yang, Ning Ma, Moshi Song, Shaoshao Zhang, Jie Wu, Feng Cao, Yongjun Wang · 发表于：Circulation · 年份：2024 · DOI：10.1161/circulationaha.123.065213 · 被引用次数：30 · 研究领域：Cardiac Valve Diseases and Treatments、Parathyroid Disorders and Treatments、Congenital heart defects research

BACKGROUND: Calcification of the aortic valve leads to increased leaflet stiffness and consequently results in the development of calcific aortic valve disease (CAVD). However, the underlying molecular and cellular mechanisms of calcification remain unclear. Here, we identified a novel aortic valve calcification-associated PIWI-interacting RNA (piRNA; AVCAPIR) that increases valvular calcification and promotes CAVD progression. METHODS: Using piRNA sequencing, we identified piRNAs contributing to the pathogenesis of CAVD that we termed AVCAPIRs. High-cholesterol diet–fed ApoE –/– mice with AVCAPIR knockout were used to examine the role of AVCAPIR in aortic valve calcification (AVC). Gain- and loss-of-function assays were conducted to determine the role of AVCAPIR in the induced osteogenic differentiation of human valvular interstitial cells. To dissect the mechanisms underlying AVCAPIR-elicited procalcific effects, we performed various analyses, including an RNA pulldown assay followed by liquid chromatography-tandem mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing. RNA pulldown and RNA immunoprecipitation assays were used to study piRNA interactions with proteins. RESULTS: We found that AVCAPIR was significantly upregulated during AVC and exhibited potential diagnostic value for CAVD. AVCAPIR deletion markedly ameliorated AVC in high-cholesterol diet–fed ApoE –/– mice, as shown by reduced thickness and calcium deposition in the aortic valv...