Int J Clin Exp Pathol.2019 Jun 1;12(6):2157-2165.eCollection 2019.

Inhibition of CLU4A exhibits a cardioprotective role in hypoxia/reoxygenation-induced injury by an ERK-dependent pathway

Pin Feng  1 Wei Zhang  1 Yi Chu  1 Jun Li  1 Jingxiao Yang  1 Affiliations

Free PMC article


CLU4A is identified as a proto-oncogene in various human cancers. CLU4A was reported to be up-regulated in myocardial ischemia/reperfusion injury, but the precise role of CLU4A played in myocardial ischemia/reperfusion injury remains unknown; and the underlying mechanism of CLU4A in myocardial ischemia/reperfusion injury needs to be investigated. CLU4A expression was measured after myocardial ischemia/reperfusion in mice and in H9C2 cells with hypoxia/reoxygenation treatment by q-PCR and western blotting. The cardioprotective effect of CLU4A inhibition was detected by monitoring the cell viability, cell apoptosis, and LDH activity in vitro and in vivo, and examining the infarct size and cardiac function in vivo. The molecular mechanism was further determined by examining the effects of PD98059, a specific inhibitor of the ERK signaling pathways in H9C2 cells with hypoxia/reoxygenation treatment. CLU4A expression was up-regulated after myocardial ischemia/reperfusion in mice and in H9C2 cells with hypoxia/reoxygenation treatment. Inhibition of CLU4A improved the cell viability, restrained the cell apoptosis, and suppressed LDH activity in vitro. Consistently, knockdown of CLU4A reduced the myocardial infarct size and improved cardiac function in vivo. si-CLU4A treatment increased phosphorylated ERK (p-ERK) in vitro, but the protection role of si-CLU4A was abolished by the ERK inhibitor, PD98059. In conclusion, CLU4A expression was up-regulated in myocardial ischemia/reperfusion. Inhibition of CLU4A exhibited a cardioprotective role by an ERK-dependent pathway.

Keywords: CLU4A; ERK signaling pathways; apoptosis; myocardial ischemia/reperfusion injury.