Shear stress inhibits cardiac microvascular endothelial cells apoptosis to protect against myocardial ischemia reperfusion injury via YAP/miR-206/PDCD4 signaling pathway.
Cardiac microvascular endothelial cells (CMECs), derived from coronary circulation microvessel, are the main barrier for the exchange of energy and nutrients between myocardium and blood. However, microvascular I/R injury is a severely neglected topic, and few strategies can reverse this pathology. In this study, we investigated the mechanism of shear stress in microvascular I/R injury, and try to elucidate the downstream signaling pathways that inhibit CMECs apoptosis to reduce I/R injury. Our results demonstrated that shear stress inhibited the apoptosis protein, increased PECAM-1 expression and eNOS phosphorylation in hypoxia reoxygenated (H/R) CMECs. The mechanism of shear stress was related to up-regulated expression of YAP, the increased number of YAP entering the nucleus by dephosphorylation, the reduced number of TUNEL positive cells, increased miR-206 and inhibited protein level of PDCD4 in CMECs. However, siRNA-mediated knockdown of YAP abolished the protective effects of shear stress on CMECs apoptosis, similar results obtained from administration with AMO-miR-206, and also prevented PDCD4 (target gene of miR-206) increasing when treatment with both AMO-miR-206 and mimics-miR-206. In vivo, restoring the blood fluid with nitroglycerin (NTG) to mimic in vitro shear stress levels, which subsequently improved cardiac function, reduced infarcted area, lowered microvascular perfusion defects. Functional investigations clearly illustrated that increased the protein expression of PECAM-1 and eNOS phosphorylation, activated YAP, strengthened miR-206 expression, and suppressed PDCD4 expression. In summary, this study confirmed that shear stress reversed CMECs apoptosis, relieved microvascular I/R injury, the mechanism of which involving through YAP/miR-206/PDCD4 signaling pathway to finally suppress myocardial I/R injury.
['Zhang|Qianlong|Q|', 'Cao|Yonggang|Y|', 'Liu|Yongsheng|Y|', 'Huang|Wei|W|', 'Ren|Jing|J|', 'Wang|Peng|P|', 'Song|Chao|C|', 'Fan|Kai|K|', 'Ba|Lina|L|', 'Wang|Lixin|L|', 'Sun|Hongli|H|']
D000818:Animals D017209:Apoptosis D051017:Apoptosis Regulatory Proteins D002470:Cell Survival D002478:Cells, Cultured D042783:Endothelial Cells D057809:HEK293 Cells D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D008297:Male D035683:MicroRNAs D055806:Microvessels D015428:Myocardial Reperfusion Injury D051381:Rats D017208:Rats, Wistar D033081:Shear Strength D015398:Signal Transduction D000091102:YAP-Signaling Proteins
Shear stress Cardiac microvascular endothelial cells Apoptosis Ischemia reperfusion injury YAP miR-206