Abstract 15179: Mir-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart
The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. Recently, we reported that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism that triggers RGS4 degradation and thus activates Gβγ/PI3Kγ/Akt/mTORC1 pathway. Interestingly, further studies of this novel mechanism reveal the specific up-regulation of miR-182 in hypertrophic hearts. Our hypothesis is that miR-182 modulates hypertrophic response and preserves cardiac function in hypertrophied myocardium.
Methods: include cell culture systems and cardiac-specific transgenic mouse models. We used transgenic, conditional overexpression of placental growth factor (PlGF) to stimulate myocardial angiogenesis, and concomitant transgenic expression of PlGF and RGS4 in cardiomyocytes or transgenic expression of PlGF in eNOS-/- mice to inhibit the hypertrophic response.
Results: Comparative analysis of miRNA arrays in hearts of PlGF, PlGF/RGS4 and control mice showed changes in miR-182, miR-1946b, miR-21, miR-130b, miR-146b, miR-669i and miR-323-5p expression. qRT-PCR analysis confirmed a 4-fold increase of miR-182 expression in PlGF mice compared with PlGF/RGS4, PlGF-eNOS-/- and control mice. The induction of miR-182 expression in PlGF mice was concurrent with myocardial hypertrophy and subsequent to angiogenesis in heart. Consistent with qPCR data, in situ hybridization confirmed the increase of miR-182 expression in cardiomyocytes in PlGF mice, but not in PlGF/RGS4 or control mice. The treatment of PlGF mice with anti-miR-182 normalized miR-182 expression in the heart and completely abolished the increase in heart size, as determined by echocardiography. The heart function was preserved during the antagomir treatment. Consistent with the in vivo data, miR-182 expression was increased by 1.8 folds in rat neonatal cardiomyocytes (RNCM) treated with NO donor and miR-182 mimic treatment of RNCM induced 22% increase in cell sizes. Moreover, miR-182 did not promote angiogenesis in the endothelial cell sprouting assay.
In conclusion, our data supports the hypertrophic role of miR-182 in myocardial hypertrophy subsequent to angiogenesis in heart.
- © 2013 by American Heart Association, Inc.