MicroRNA-34a-Dependent Attenuation of Angiogenesis in Right Ventricular Failure

BACKGROUND: The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1 alpha- vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure. METHODS AND RESULTS: Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1 alpha expression increased (0.12 +/- 0.01 versus 0.22 +/- 0.03, P=0.05), VEGF expression decreased (0.61 +/- 0.03 versus 0.22 +/- 0.05, P=0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10 +/- 3% versus 22 +/- 2%, P<0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1 alpha, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-beta 1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR- 34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease- related RVF, RV capillarity was decreased and miR-34a increased 5-fold. CONCLUSIONS: In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1 alpha- VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR- 34a therapeutics in patients with at-risk RVs.