AntimiR-34a to Enhance Cardiac Repair After Ischemic Injury.

Abstract

Heart disease often culminates into a decline in function and heart failure as a result of the loss of viable cardiac tissue. Given the global burden of heart disease, a lot of effort is currently dedicated toward the development of strategies that can regenerate the human heart.1 Although the heart is notoriously resistant to regeneration, recent studies have shown that it provides some opportunities to enhance heart repair by the rescue of existing cells or the formation of new cardiomyocytes. These new heart muscle cells can either originate from nonmyocyte cell types or by cardiomyocytes reentering the cell cycle. Article, see p 450 A recent study by Yang et al showed that the decline in proliferative capacity of the cardiomyocytes coincides with an elevated level of miR-34a and that an increase in miR-34a can block the regenerative potential of a neonatal heart.2 Interestingly, therapeutic inhibition of miR-34a in the setting of myocardial infarction (MI) in the adult heart increased myocyte turnover and survival, at least partially because of the regulation of prosurvival and cell cycle regulators. Although these findings present an interesting therapeutic opportunity, issues regarding the mechanism, quantity of restored tissue, cross-species conservation of the mechanism, and the off-target effects of the microRNA (miRNA) therapeutic will need to be explored in detail before moving into patients. Although the majority of postnatal cardiomyocytes transition from a proliferative to a differentiated state, a subset of myocytes maintains some regenerative potential albeit at a low capacity. Several years ago, a seminal paper from Bergmann et al showed by carbon-14 birth dating approaches that, of the several billion cardiomyocytes present in the human heart, ≈0.5% turns over every year.3 This is in agreement with the 1% cardiomyocyte turnover that was observed in the adult murine heart.4 The cell cycle …