MicroRNA-34a regulates cardiac ageing and function

Abstract

Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

Vieillissement

“…Elles suggèrent cependant que le vieillissement est associé à une altération du profil d'expression des miARN cardiaques. Un des premiers articles expérimentaux dans ce domaine a été publié par l'équipe de Stephanie Dimmeler [36]. Cette équipe a proposé que le miR-34a (microRNA-34a) favoriserait le vieillissement cardiaque en inhibant PNUTS (phosphatase-1 nuclear targeting subunit), un facteur qui maintiendrait l'intégrité des télomères, inhiberait la DDR et préviendrait l'apoptose.…”

miRNAGE-34 induces cardiac damAGE

“…In a recent paper in Nature, Boon and colleagues elegantly show upregulation of miR-34a in the heart during aging in humans and mice [1]. Corroborating evidences are derived from work on mice with loss of Ku80.…”

“…Interestingly, miR-34a level is increased in the heart of Ku80 heterozygous and homozygous knockout mice. In the latter, inhibition of miR-34a expression by systemic use of a miRNA inhibitor retarded agedependent cardiac deterioration [1].…”

“…Cardiac aging is associated with increased apoptosis, fibrosis deposition, hypertrophy and reduced function. All these features could be corrected by systemic use of miR-34a inhibitors [1] (Figure 1). Whether this miRNA is more upstream than others in aging processes remains to be determined as other miRNAs involved in cardiac aging have been identified [3].…”

“…miR-34 level is elevated in the mouse infarcted heart [1,4], where its inhibition proved therapeutically useful by acting on the aforementioned processes and additionally promoting post-ischemic reparative angiogenesis (Figure 1). Similar beneficial effects were evident using a miR-34a knockout model.…”