• Yongjun Wang, Xiaoxiong Xiao, Tingwen Zhou, Dong Han, and Nianguo Dong.
• Department of Cardiovascular Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
• J. Thorac. Cardiovasc. Surg. 2020 May 1; 159 (5): 1742-1753.e7.

ObjectiveAortic valve calcification is common in aging populations without effective pharmacologic interventions. Our previous in vitro data revealed a critical role for long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 as a positive regulator of osteogenic differentiation in aortic valve calcification pathogenesis. The current study sought to determine the mechanism by which metastasis-associated lung adenocarcinoma transcript 1 is regulated in aortic valve calcification.MethodsThe stability assay was used to examine the effect of human antigen R on metastasis-associated lung adenocarcinoma transcript 1 expression. Aortic valves from patients with aortic stenosis and normal controls were subjected to determination of RNA-binding protein human antigen R expression. Mineralized bone matrix formation was assessed by Alizarin Red staining. The interaction between metastasis-associated lung adenocarcinoma transcript 1 and miR-191-3p was confirmed via RNA pull-down, luciferase reporter, and RNA-binding protein immunoprecipitation assays.ResultsIn cultured human aortic valvular interstitial cells, we found human antigen R enhanced metastasis-associated lung adenocarcinoma transcript 1 stability and thus increased its concentration. Moreover, human antigen R was significantly upregulated in human calcific aortic valves and valvular interstitial cells after osteogenic induction. Human antigen R partly relied on metastasis-associated lung adenocarcinoma transcript 1 to positively regulate osteogenic differentiation of valvular interstitial cells. Luciferase reporter assays validated human antigen R as the direct target of miR-191-3p. Metastasis-associated lung adenocarcinoma transcript 1 positively regulated the expression of human antigen R through sponging miR-191-3p.ConclusionsThis study demonstrates the existence of a regulatory loop between metastasis-associated lung adenocarcinoma transcript 1 and human antigen R during osteogenic differentiation of valvular interstitial cells. Our findings provide novel mechanistic insights into a critical role of human antigen R in the aortic valve calcification progression and shed new light on RNA-binding protein-directed diagnostics and therapeutics in aortic valve calcification.Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

31 keywords...

hide…