MicroRNA-146a regulates angiogenesis and functional regeneration after myocardial infarction

Abstract Background The growth or regeneration of new blood vessels is critical for physiological angiogenesis and for tissue repair in response to injury, such as myocardial infarction. However, the mechanisms underlying the angiogenic processes and, specifically, the regulation of neo-vascularization by microRNAs are not well understood. Purpose To study the potential beneficial role of miRNA-146a in vessel regeneration after myocardial infarction. Methods Mice were subjected to myocardial infarction or hind limb ischemia and vascular development was followed in zebra fish. microRNA-146a was blocked or overexpressed in endothelial cells in vitro or in mice or zebra fish in vivo. Furthermore, Blood samples from patients with ST-elevation myocardial infarction (STEMI) were studied for miR-146a expression. Results MicroRNA-146a was upregulated in the ischemic hind limb following ligation of the femoral artery and in the ischemic myocardium in male C57BL/6 mice following ligation of the left anterior descending (LAD) artery, as well as in patients with STEMI. In vitro, overexpression of microRNA-146a significantly attenuated endothelial cell proliferation and migration, abolished endothelial capillary network formation, and inhibited cell sprouting from endothelial spheroids. In contrast, microRNA-146a silencing had opposite effects. Mechanistically, Nox4, Notch1, and nRas were identified by in silico prediction and microarray mRNA expression analysis, and validated as direct targets and effector molecules of microRNA-146a in endothelial cells according to mRNA and protein expression profiles, as well as luciferase gene reporter assays and respective rescue experiments. In zebrafish, overexpression of microRNA-146a inhibited the development of the trunk vasculature. Blocking the upregulation of endothelial microRNA-146a in mice,using specific inhibitors, resulted in significantly enhanced 1 angiogenesis and revascularization both in an ischemic hind limb model and in the infarcted myocardium. This was accompanied by a significantly reduced myocardial infarct size and preserved cardiac function post MI. Conclusions Our findings identify microRNA-146a as a critical regulator of angiogenesis and vascular regeneration. Inhibition of microRNA-146a may represent an attractive strategy for the angiogenic therapy of ischemic tissue diseases. Funding Acknowledgement Type of funding source: None