miR-214 is Stretch-Sensitive in Aortic Valve and Inhibits Aortic Valve Calcification

• Type of Material: Article
• Authors: Md. Tausif Salim, Georgia Institute of Technology; Joan Fernandez Esmerats, Georgia Institute of Technology; Sivakkumar Arjunon, Georgia Institute of Technology; Nicolas Villa-Roel, Georgia Institute of Technology; Robert Nerem, Emory University; Hanjoong Jo, Emory University; Ajit Yoganathan, Emory University
• Language: English
• Date: 2019-04-01
• Publisher: Springer
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Biomedical Engineering Society
• Final Published Version (URL): http://dx.doi.org/10.1007/s10439-019-02206-3
• Title of Journal or Parent Work: Annals of Biomedical Engineering
• Volume: 47
• Issue: 4
• Start Page: 1106
• End Page: 1115
• Grant/Funding Information: We would like to acknowledge NIH grant R01HL119798 for funding support.
• Keywords: Osteogenic differentiation; Engineering; Engineering, Biomedical; Microrna therapeutics; miR-214; Replacement; Transcatheter; Aortic valve; Science & Technology; Technology; Calcification; Cyclic stretch; Inflammation; Endoplasmic reticulum stress; Gene expression; Apoptosis; Disease; Mesenchymal stem-cells
• Research Categories: Engineering, Biomedical; Biology, Genetics; Chemistry, Biochemistry; Biology, Molecular

Abstract

miR-214 has been recently found to be significantly downregulated in calcified human aortic valves (AVs). ER stress, especially the ATF4-mediated pathway, has also been shown to be significantly upregulated in calcific AV disease. Since elevated cyclic stretch is one of the major mechanical stimuli for AV calcification and ATF4 is a validated target of miR-214, we investigated the effect of cyclic stretch on miR-214 expression as well as those of ATF4 and two downstream genes (CHOP and BCL2L1). Porcine aortic valve (PAV) leaflets were cyclically stretched at 15% for 48 h in regular medium and for 1 week in osteogenic medium to simulate the early remodeling and late calcification stages of stretch-induced AV disease, respectively. For both stages, 10% cyclic stretch served as the physiological counterpart. RT-qPCR revealed that miR-214 expression was significantly downregulated during the late calcification stage, whereas the mRNA expression of ATF4 and BCL2L1 was upregulated and downregulated, respectively, during both early remodeling and late calcification stages. When PAV leaflets were statically transfected with miR-214 mimic in osteogenic medium for 2 weeks, calcification was significantly reduced compared to the control mimic case. This implies that miR-214 may have a protective role in stretch-induced calcific AV disease.