Inhibition of Let‐7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice

Abstract

The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2–positive fibroblasts, while the number of c-kit+ cardiac stem cells and Ki-67+ proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure.

Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin

“…It may be due to that members of let-7 family are located on different chromosomes (genes). Previous studies have reported that upregulation of let-7a is involved in cardiac hypertrophy 20 and miR-98/let-7 mediates the antihypertrophic effect through Trx1 22. These studies demonstrated the anti-hypertrophic property of let-7a and miR-98/let-7, which is consistent with our results.…”

“…Recent studies demonstrated that miRNAs play a critical role in regulation of cardiac developmental and cardiovascular diseases 13-15. It has been reported that let-7 plays a crucial role in multiple biologic functions, including tumor suppression 16, 17, axon regeneration 18, arrhythmia inhibition 19, and cardiac fibrosis and apoptosis reduction 20. A study by Gray et al showed that upregulation of let-7 may be involved in regulation of cardiac hypertrophy process in rats 21.…”

The transcardiac gradient of cardio‐microRNAs in the failing heart

“…The detailed involvement of the let‐7 family in cardiovascular disease is reviewed elsewhere . Highlighted are higher levels of some let‐7 miRNAs in endothelial to mesenchymal transition, possibly contributing to cardiac fibrosis, and inhibition of let‐7 in vivo preserving cardiac function post‐infarction and reducing fibrosis . The miR‐15 family was previously found to govern cardiomyocyte proliferation and binucleation during development, by inducing cell cycle arrest .…”

A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1

“…Efforts to downregulate let-7 have produced discordant results. Aguirre et al described improved systolic function with combined intracardiac injection of anti-miR-let-7a/c and anti-miR-99/100 late in the course of experimental myocardial infarction, associated with evidence of increased cardiomyocyte mitosis [28]; Tolonen reported that intravenous infusion of a miR-let-7c antagomiR 4 weeks after coronary occlusion prevented post-MI remodeling, associated with reduced apoptosis and fibrosis[76]. These conflicting results could be due to the significant difference in timing of intervention in these latter studies, and possibly also in model systems and microRNA manipulation strategies.…”