Abstract 12924: Inhibition of microRNA-34a Protects against Aging and Progeria Associated Cardiac Dysfunction by Interfering with Telomere Shortening and DNA Damage Response Pathways
Aging is the major risk factor for complications like acute myocardial infarction (AMI) and chronic heart failure. The mechanisms involved in cardiovascular aging are poorly understood, but miRNAs are emerging as key biological regulators. We investigated the mRNA and miRNA expression in hearts of aged mice (18 months) and young mice (6 weeks). Amongst the significantly upregulated miRNAs in aged hearts was the entire miR-34 family. MiR-34a is highly expressed and significantly correlates with age in human hearts as well (p=0.004). Inhibition of miR-34a in 18 month old mice using specific antagomirs against miR-34a (Ant-34a) reduced apoptosis in the heart (41.8±12.5%, P<0.05). Consistently, progeria-induced cardiac contractile dysfunction in DNA damage-prone KU80-/- mice was also ameliorated by miR-34a inhibition (Absolute ejection fraction (EF) increase: 17.7±2.1%). Moreover, 18 month old miR-34a-/- mice displayed superior cardiac contractile function (EF: 63.5±2.7%) and reduction in apoptosis and hypertrophy, compared to wt littermates (EF: 52.3±2.2%). We also found that AMI induces miR-34a in the heart and that silencing of miR-34a improves recovery after AMI. SIRT1 is one of the targets of miR-34a, but AMI experiments with SIRT1+/- mice showed that the beneficial effects of miR-34a inhibition do not solely rely on SIRT1. Next, we identified novel potential targets of miR-34a, of which PNUTS (PPP1R10) is most strongly downregulated in aged hearts (89.4±4.2% inhibition, p<0.05). Regulation of PNUTS by miR-34a was confirmed in vitro and in vivo. PNUTS interacts with the telomere regulator and DNA damage response (DDR) protein TRF2. Overexpression of PNUTS abrogated miR-34a-dependent apoptosis, DDR and telomere erosion in cardiomyocytes as measured by P-Chk2, as well as Q-FISH and Q-PCR telomere analysis. The prevention of telomere shortening and Chk2 phosphorylation by PNUTS was dependent on TRF2 as shown by TRF2 silencing and mutation of the TRF2 binding site in PNUTS. Together, these results identify miR-34a as a key regulator of cardiac function in aging, through the attenuation of the telomere and DDR regulator PNUTS. Therapeutic inhibition of miR-34a constitutes a new strategy to avert cardiac dysfunction during aging and after AMI.
- © 2012 by American Heart Association, Inc.