MicroRNA-34a Plays a Key Role in Cardiac Repair and Regeneration Following Myocardial Infarction

Abstract

Rationale In response to injury, the rodent heart is capable of virtually full regeneration via cardiomyocyte proliferation very early in life. This regenerative capacity, however, is diminished as early as one week post-natal and remains lost in adulthood. The mechanisms that dictate post injury cardiomyocyte proliferation early in life remain unclear. Objective To delineate the role of miR-34a, a regulator of age-associated physiology, in regulating cardiac regeneration secondary to myocardial infarction (MI) in neonatal and adult mouse hearts. Methods and Results Cardiac injury was induced in neonatal and adult hearts through experimental MI via coronary ligation. Adult hearts demonstrated overt cardiac structural and functional remodeling, whereas neonatal hearts maintained full regenerative capacity and cardiomyocyte proliferation, and recovered to normal levels within one week time. As early as one week post-natal, miR-34a expression was found to have increased and was maintained at high levels throughout the lifespan. Intriguingly, seven days following MI, miR-34a levels further increased in the adult but not neonatal hearts. Delivery of a miR-34a mimic to neonatal hearts prohibited both cardiomyocyte proliferation and subsequent cardiac recovery post-MI. Conversely, locked nucleic acid-based anti-miR-34a treatment diminished post-MI miR-34a upregulation in adult hearts and significantly improved post-MI remodeling. In isolated cardiomyocytes, we found that miR-34a directly regulated cell cycle activity and death via modulation of its target genes, including Bcl2, Cyclin D1, and Sirt1. Conclusions miR-34a is a critical regulator of cardiac repair and regeneration post-MI in neonatal hearts. Modulation of miR-34a may be harnessed for cardiac repair in adult myocardium.

Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin

“…An elevation in miR-34a expression has also been linked to reduced sirtuin1 expression in obesity and arteries from aged human and mice (Li et al, 2011;Choi et al, 2013;Fu et al, 2014) and accelerated apoptosis of cardiomyocytes in neonatal and adult mouse hearts (Yang et al, 2015). In conclusion, and as summarized in Fig.…”

MicroRNA-449a Inhibition Protects H9C2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Targeting the Notch-1 Signaling Pathway

“…Moreover, a number of studies recently indicated the downregulation of the expression of miR-449 in various human malignancies, including lung cancer, prostate cancer, and adrenal hyperplasia [28, 29]. miR-34 has been reported to function in cardiovascular disorders by regulating apoptosis, telomere attrition, DNA damage, and inflammatory response [30-33]. However, no study has reported the involvement of miR-449 in the cardiovascular disease.…”

Therapeutic potential of targeting microRNAs to regulate cardiac fibrosis: miR-433 a new fibrotic player

“…Each of these miRNAs, or their family members, have previously been shown to be elevated in hearts of cardiac stress mouse models associated with fibrosis (e.g., MI, pressure overload, dilated cardiomyopathy and atrial fibrillation), and targeting these miRNAs was effective in preventing or attenuating fibrosis in vivo (5,(7)(8)(9)(10)(11)(12)(13)(14). Other studies have identified numerous additional miRNAs dysregulated in cardiac fibrotic models.…”