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

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 hours in regular medium and for one 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 stretchinduced calcific AV disease.

Mechanisms of heart valve development and disease

“…A study using human aortic VECs demonstrated that that shear stress may regulate Notch1 signaling (White et al, 2015). Additional in vitro studies have suggested that shear-sensitive microRNAs (miRNAs) may also be involved in CAVD (Holliday et al, 2011;Fernandez Esmerats et al, 2019;Salim et al, 2019). Another study identified two families with early onset progressive heart valve disease caused by a homozygous mutation in ADAMTS19 (Wünnemann et al, 2020).…”

Role of hypoxia inducible factor HIF-1⍺ in heart valves

“…The different patterns of blood flow experienced either side of the aortic valve have also been implicated in expression of HIF-1 α . It has been shown that disturbed patterns of flow, characteristic of the aortic side of the valve, are associated with expression of HIF-1 α , miR-483, ubiquitin E2 ligase C and von Hippel-Lindau protein, which have all been shown to be flow-sensitive molecules 52 . Under conditions of disturbed flow, von Hippel-Lindau Protein is degraded by ubiquitin E2 Ligase C, causing HIF-1 α levels to rise.…”

Effect of Static and Dynamic Stretching on Corneal Fibroblast Cell

“…Mechanical stress is an important environmental stimulus for regulating cell physiology and morphology [10][11][12][13][14]. The effects of cyclic stretching, in addition to tensile stress and fluid shear stress, have been investigated in various cell types [15][16][17][18][19][20][21][22][23][24][25][26][27].…”