Ghrelin protects against cell death in myocardial ischaemia: Emerging role of microRNA.

Acute myocardial infarction (MI) accelerates cardiomyocyte apoptosis, which underpins ventricular remodelling and dysfunction. The hormone ghrelin mitigates this remodelling, but the mechanisms remain unclear. Specific microRNAs (miRs) are key modulators and reliable biomarkers of early-stage apoptosis. We hypothesized that ghrelin targets anti-apoptotic miR-499 and miR-133 following MI to suppress cardiac apoptosis and thus mitigate cardiac dysfunction. C57/B6 mice received an injection of ghrelin (150 µg/kg, s.c.) or saline following left anterior descending coronary artery ligation (MI). Plasma levels of miR-499 and miR-133 at 3 or 24 h post-MI were measured using real-time PCR. Echocardiography and TUNEL staining were used to assess progressive cardiac function/structure and cardiomyocyte apoptosis, respectively. Myocardial ischaemia adversely decreased the levels of anti-apoptotic miR-499 by 3 h post-MI and increased the proportion of TUNEL-positive apoptotic cardiomyocytes by 24 h post-MI, contributing to cardiac remodelling and dysfunction by 2 weeks post-MI. Ghrelin prevented this MI-induced decrease in miR-499 by 3 h post-MI, then further increased the levels of miR-499 and miR-133 by 24 h. These ghrelin-mediated changes in microRNA were associated with a significant decrease in cardiomyocyte apoptosis and, consequently, significantly improved cardiac function and structure by 2 weeks post-MI. These results highlight miRs as effective biomarkers for the early detection of ischaemia-induced apoptotic signalling. Moreover, ghrelin appears to mitigate ischaemia-induced apoptosis by increasing the levels of anti-apoptotic miR-499 and miR-133, further solidifying ghrelin as a new therapeutic strategy for the clinical treatment of heart failure.