Abstract 20371: Non-Cardiomyocyte MicroRNA-34a Mediates Dysregulation of Angiogenesis in RV Failure

Introduction: The right ventricle (RV) is uniquely at risk in patients with complex congenital heart disease (CHD) involving right-sided obstructive lesions. In the left ventricle (LV) angiogenesis is a key adaptation to pressure overload, induced during adaptive hypertrophy via Hif-1α and VEGF, and declining with LV failure. In contrast, early capillary rarefaction occurs in RV hypertrophy (RVH), the mechanism of which is unknown. We hypothesize that microRNA (miR) 34a is responsible for the attenuated angiogenic response in RVH and RV failure (RVF). Methods: Adult, male FVB mice were subject to pulmonary artery banding (PAB) to induce RVH and RVF and compared to sham-operated controls. In vitro miR overexpression studies using lipofectamine miR-34a and in vivo miR inhibition studies using LNA-antimiR-34a (25mg/kg IP) were performed. RNA and protein expression was evaluated from the RV free wall. Student’s t test was used for two group comparisons and Kaplan Meier for survival analysis. Data are presented as mean±SEM (*p Results: miR-34a is upregulated (6.5 fold) in RVH/RVF and is associated with capillary rarefaction (1.5±0.1 vs. 1.2±0.1*) and decreased VEGF signaling. miR-34a originates from fibroblasts and endothelial cells in RVH/RVF. miR-34a overexpression in endothelial cells induces cell senescence (10±1 vs. 30±4%*) by suppressing SIRT1 expression (1.8±0.5 vs. 0.8±0.1*), decreases proliferation (0.5±0.04 vs. 0.3±0.01*) and decreases tube formation by 50% via suppression of Hif-1α (0.9±0.1 vs. 0.5±0.02*), VEGF A (0.7±0.2 vs. 0.5±0.03*), VEGF B (0.4±0.1 vs. 0.1±0.01*) and VEGFR2. AntimiR-34a suppresses miR-34a in PAB, reverses the decrease in capillarity and VEGF, and improves survival half-time by 44%*. miR-34a is also increased in children with RVF (2-fold) and capillarity is decreased compared to those with RVH. Conclusions: Capillary rarefaction is a feature of RVH/RVF in murine models of CHD and children with CHD. Capillary rarefaction is due to the uncoupling of HIF-1α and VEGF signaling which maybe mediated by non-cardiomyocyte miR-34a. Inhibition of miR-34a rescues capillarity and delays the onset of heart failure thereby raising its potential for therapeutic manipulation and translation into clinical practice.