Abstract 20667: Cardiomyocyte miR-29 Promotes Cardiac Remodelling
Cardiac hypertrophy is the response of the heart to several stimuli such as myocardial infarction and volume or pressure overload. MicroRNAs have been shown to play an important role in cardiac disease. miR-29 is predicted to target a number of extracellular matrix genes including collagens and matrix metallopeptidases (MMP). Whereas previous studies have focused on the role of miR-29 in cardiac fibroblasts and in the healthy heart, the role of miR-29 in cardiomyocytes and during cardiac disease remained unclear. In the present study we investigated the role of miR-29 in the myocardium by chemical and genetic manipulation of miR-29 in vitro and in vivo.
We found that miR-29 was preferentially expressed in cardiomyocytes rather than in cardiac fibroblasts in adult rodents and that their expression was transiently increased during the early phase of cardiac hypertrophy induced by transverse aortic constriction (TAC) in mice. Furthermore miR-29 promoted hypertrophic growth of primary cardiomyocytes in vitro (CM mean cell area (μm2): miR-control 136±5; miR-29a: 290±30) whereas antagonization of miR-29 with locked nucleic acid-modified antisense molecules (LNA-29) efficiently impeded phenylephrine-induced hypertrophy in vitro. Genetic deletion of miR-29 in gene targeted mice prevented cardiac hypertrophy and fibrosis induced by TAC. To overexpress miR-29 specifically in cardiomyocytes, an AAV9 construct carrying miR-29a (AAV-miR-29a) was injected intravenously into mice that were subjected to TAC or Sham surgery. AAV-miR-29a significantly increased TAC-induced cardiac hypertrophy (heart weight-to-tibia length ratio), which was paralleled by an increase of the average cardiomyocyte cross-sectional area. Conversely, LNA-29 protected mice from cardiac remodeling induced by TAC (HW/TL ratio: Sham: 5.27±0.3; TAC control: 9.4±0.1; TAC LNA-29: 6.5.±0.4). Finally, a series of bioinformatic and biochemical analyses revealed that miR-29 directly targets the GSK3β/NFAT pathway in cardiomyocytes and thereby promotes cardiomyocyte hypertrophy.
Together, our results indicate the members of the miR-29 family as important regulators of cardiomyocyte hypertrophy and as potential therapeutic targets in myocardial disease.
Author Disclosures: Y. Sassi: None. P. Avramopoulos: None. D. Ramanujam: None. B. De Strooper: None. S. Engelhardt: None.
- © 2014 by American Heart Association, Inc.