Role of microRNA 214 in cyclic stretch induced aortic valve pathogenesis

Calcific aortic valve disease (CAVD) is one of the most prevalent valvular diseases among the elderly population. Unfortunately, there are no therapeutic drugs available to treat this disease. In this regard, mechanosensitive miRNAs have been considered as potential therapeutic candidates for CAVD, due to their role in modulating gene expression. microRNA 214 (miR-214) is a major miRNA which is significantly downregulated in calcified aortic valves (AVs). Previously, miR-214 has been shown to be shear-sensitive in AV. However, the effect of cyclic stretch on miR-214 expression and its functional effect in AV are poorly understood. Hence, this work aims to evaluate the effect of cyclic stretch on the expression of miR-214 and one of its well-known targets (ATF4) and downstream genes (CHOP and BCL2L1) in porcine AVs ex vivo. Also, the effect of miR-214 overexpression on porcine AV calcification is evaluated. This would give a better understanding on the potential therapeutic role of miR-214 in CAVD.M.S

MicroRNAs and Messenger RNAs in Cyclic Stretch Induced Aortic Valve Pathogenesis

Calcific aortic valve disease (CAVD) is one of the most prevalent valvular diseases among the elderly population. Unfortunately, there are no therapeutic drugs available to treat this disease. Since calcified aortic valves (AVs) have distinct miRNA and gene expression profiles compared to healthy AVs, microRNA (miRNA) and messenger RNA (mRNA) based therapies hold a lot of promise as potential drugs. In this regard, mechanosensitivity of AV calcification-specific miRNAs and mRNAs can serve as a critical criterion in identifying the most effective candidates, as it has been shown that altered mechanical environment plays a key role in AV pathogenesis. To this day, majority of the studies have focused on disturbed flow-induced changes in miRNA and mRNA expression related to CAVD. However, identification and functional description of stretch-sensitive miRNAs and mRNAs in CAVD are poorly studied. Hence, this work aims to identify and functionally describe AV calcification-specific miRNAs and mRNAs that are stretch-sensitive. Our hypothesis is that stretch-sensitive miRNAs and mRNAs play a significant role in the pathogenesis of AV calcification; consequently, overexpression or inhibition of these miRNAs and mRNAs are potential candidates for therapeutic application. To test this hypothesis, the following aims are proposed: (1) investigate the effects of physiological and pathological cyclic stretch on miRNA expression in AV, and (2) investigate the effects of physiological and pathological cyclic stretch on mRNA expression in AV. This research work will help in identifying important stretch-sensitive miRNAs and mRNAs as potential therapeutic candidates for CAVD.Ph.D