Increasing evidence has indicated that lncRNAs and miRNAs play important roles in the pathogenesis of myocardial ischemic and reperfusion (I/R) injury. This study investigated the potential roles and underlying molecular mechanisms of lncRNA H19 and H19-derived miR-675 in regulating myocardial I/R injury in vitro and in vivo. The results showed that expression of H19 and H19-derived miR-675 was upregulated in cardiomyocytes exposed to oxygen-glucose deprivation and reperfusion. Knockdown of H19 increased cell viability, reduced cell apoptosis, decreased inflammatory cytokines (IL-1β, TNF-α and IL-6), inhibited oxidative stress, downregulated p-IκB-α and p-p65, and upregulated expression of Nrf2 and HO-1. All of these effects were partly reversed by overexpression of miR-675. Furthermore, we found that PPARα was a target gene of miR-675 and that H19 negatively regulated PPARα expression via miR-675. By inhibiting PPARα, the biological effects of miR-675 or H19 inhibition on cellular functions (apoptosis, inflammation and oxidative stress) were at least partially reversed. Moreover, knockdown of H19 significantly reduced infarct size, increased left ventricular systolic pressure, and decreased left ventricular end-diastolic pressure in a mouse model of myocardial I/R. Taken together, these data indicate that H19 inhibition protects the heart against myocardial I/R injury, which may be partly attributed to regulation of the miR-675/PPARα axis.
Keywords: Apoptosis; Inflammation; Myocardial ischemic-reperfusion injury; PPARα; lncRNA H19; miR-675.
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