LncRNA KCNQ1OT1 aggravates myocardial ischemia/reperfusion injury by mediating the EZH2/TIMP-3 axis

This study focused on discussing the mechanism of lncRNA KCNQ1OT1 mediating histone methylase enhancer of zeste homolog 2 (EZH2) to repress tissue inhibitor of metalloproteinase-3 (TIMP-3) expression in myocardial ischemia/reperfusion injury (MI/RI). Ischemia-hypoxia hypoxia/reoxygenation (H/R) models were successfully constructed by utilizing primary cardiomyocytes. KCNQ1OT1 and TIMP-3 expression in cardiomyocytes was tested. The proliferative capacity of the cells was assessed. The changes of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) contents in the supernatant of primary cardiomyocytes and Caspase-3 activity were measured. The apoptosis of primary cardiomyocytes was tested. The interactions of KCNQ1OT1, EZH2 and TIMP-3 were verified. Compared to the control group, KCNQ1OT1 expression levels, supernatant LDH and MDA levels, Caspase-3 activity, and cardiomyocyte apoptosis rate in the H/R group were elevated, and cell viability, TIMP-3 expression, and supernatant SOD levels were decreased. After KCNQ1OT1 interference or TIMP-3 overexpression, LDH and MDA levels, Caspase-3 activity, and cardiomyocyte apoptosis rate were reduced, while cell viability, TIMP-3 expression, and SOD levels were raised. Interfering TIMP-3 reversed the ameliorative effects of KCNQ1OT1 downregulation on MI/RI. Mechanistically, KCNQ1OT1 inhibited TIMP-3 expression by recruiting EZH2 to the TIMP-3 promoter region. Interference with KCNQ1OT1 could block EZH2 to the TIMP-3 promoter region and thereby up-regulate TIMP-3 expression, which possesses an ameliorative impact on MI/RI.