Abstract 20168: Enhanced Endothelial Nitric Oxide Production and Cardiac Dysfunction in an Inducible Endothelial-Specific miR-130a Mouse Model

Abstract

Introduction: MicroRNA-130a (miR130a) has been shown to be important in cardiovascular gene regulation in both normal and diseased states. We recently reported on the regulation of connexin43 by miR130a. Methods: We created an inducible mouse model to express miR-130a in endothelial cells under the control of the VE-cadherein promoter (VE-cad-miR130a). Overexpression of miR-130a was initiated in adult mice at weaning, approximately 4 weeks post-birth. Results: Survival analysis revealed >50% mortality by 9 weeks of age with overexpression of miR-130a. By 9 weeks of age, LV function was reduced (26.4% ± 4 vs 33.6% ± 6 in controls, p<0.001, n=10). Prior to the onset of LV dysfunction; we found numerous abnormalities in cardiac function. First, we noted significant bradycardia on ambulatory telemetric recordings (389bpm ± 90 vs 534bpm ± 72 in controls, p<0.0001, n=3). Moreover, the cardiac response to β-AR stimulation was blunted in VE-Cad-miR130a mice relative to control when challenged with isoproterenol. Interestingly, sinus node recovery time was significantly prolonged, supportive of sinus node dysfunction. While predominately in sinus rhythm, we found episodes of spontaneous atrial tachyarrhythmias, which were confirmed on invasive electrophysiologic testing. To investigate further, we performed patch clamp measurements of action potential duration (APD) in atrial cariomyocytes. APD was significantly prolonged in VE-Cad-miR130a myocytes (APD90 325ms vs 60ms, p<0.00001, n=3). Next, we performed invasive blood measure measurements and found a significant decrease in mean arterial blood pressure (76.9mmHg ± 3 vs 94.3mmHg ± 5 in controls, p<0.01, n=4). Based on previous reports of increased nitric oxide in the setting of loss of endothelial connexin43, we found significant elevation of NO concentration in VE-Cad-miR130a. Inhibition of NO synthase via IP administration of L-NAME increased MAP in VE-Cad-miR130a to a maximum steady-state mimicking that of control mice. Conclusions: Overexpression of miR-130a in endothelial cells promotes impaired cardiovascular function and abnormal atrial conduction. These results suggest a newly identified role for endothelial miR-130a in the development of hypotension and cardiac dysrhythmias.