Targeting microRNAs to promote cardiac repair and cardiomyocyte proliferation as a potential regenerative therapeutic approach

MicroRNAs (miRNAs) have emerged as important modulators of cardiovascular biology, repair, and regeneration. miRNAs posttranscriptionally regulate the expression of a network of proteins and consequently, cardiovascular development. miRNA targeting has been shown to: (i) improve the cardiac repair capacity of patient-derived circulating or bone marrow–derived mononuclear cells (BMCs); (ii) induce pluripotent stem cells or direct cardiac reprogramming; and (iii) promote cardiomyocyte proliferation after cardiac injury. Several groups, including our group, have recently targeted miR-126 or miR-34a to improve the cardiac repair potential of circulating mononuclear cells or BMCs from patients with ischemic cardiomyopathy. Moreover, targeting of several miRNAs induced reprogramming of mouse and human cells to pluripotency, and initial experimental studies suggest that fibroblasts can be directly converted into cardiomyocytes in vivo by targeting miRNAs–a process termed direct reprogramming. Recent data suggest a marked early postnatal cardiomyocyte proliferation in response to myocardial injury. Cardiomyocyte proliferation still occurs in adults, although at a very low rate (0.5% to 1% per year). These observations have stimulated the interest in investigating therapeutic strategies to promote cardiomyocyte reentry into the cell cycle to compensate for cardiomyocyte loss after myocardial infarction. Experimental studies have shown that miR-1, miR-133a, miR-29a, and the miR-15 family repress cardiomyocyte proliferation, whereas miR-199a and miR-590 promote cardiomyocyte proliferation in injured murine hearts. Therapeutic targeting of miRNAs is being intensely examined to promote cardiac repair and regeneration, a development aided by high-throughput functional screening assays. Large animal data suggest that targeting miRNAs can improve cardiac function after injury, indicating a potential future applicability for this approach to enhance cardiac repair and regeneration in the clinical setting. L Heart Metab. 2014;65:9-14