Abstract 17163: Prolonged Increase in Endothelium-Specific NOX2-Derived Cytosolic Oxidants Exacerbates Maladaptive Cardiac Remodeling in Ischemic Myocardium

Abstract

Introduction: Global increase in reactive oxygen species (ROS) in endothelial cells (EC) plays major roles in cardiovascular disease (CVD). However, the precise role of ROS within specific compartments of ECs are not yet known. This study aims to address the role of endothelium-derived cytosolic ROS in myocardial infarction (MI). Hypothesis: We hypothesized that an extended exposure to increased NADPH oxidase 2 (NOX2)-derived cytosolic ROS in EC would result in a worse post-MI outcome. Methods: Binary conditional transgenic mice expressing NOX2 in an EC-specific manner (NOX2VE) were studied. NOX2VE mice were assigned to tetracycline (Tet)-ON (control) to turn off transgene, or without Tet as Tet-OFF, i.e. NOX2- O ver E xpressing (NOX2VE-OE) groups. After 15 weeks of Tet-ON/OFF treatment, all mice were subjected to left anterior descending (LAD) coronary artery ligation that mimics acute MI (n=10/group). Left ventricle function was assessed by echocardiography 28 days post LAD. Ejection fraction (EF), fractional shortening (FS), left ventricle mass, wall thickness, heart rate, chamber diameter and volume at systole and diastole were analyzed by Student’s t-test. Results: Echocardiographic data showed that mice subjected to an increased NOX2-derived ROS in EC (NOX2VE-OE) presented with 19.3 ± 7.7% and 20.8 ± 7.9% decrease in EF and FS, respectively (p<0.05) compared to control (NOX2VE, Tet-ON). NOX2VE-OE mice showed an increase (by 14.1 ± 3.4%, p<0.01) in diastolic posterior wall thickness (DPWT) suggesting ventricular stiffness. NOX2VE-OE group also showed increased cardiac mass (by 14.0 ± 5.4%, p<0.05), which, along with DPWT indicates hypertrophy with a likelihood to develop heart failure. Interestingly, heart rate, systolic and diastolic chamber volume and diameters, stroke volume, and cardiac output showed no differences between the groups (p>0.05). Conclusions: Together, these results suggest that prolonged exposure to increased cytosolic ROS in coronary EC results in worse cardiac performance and myocardial stiffness, leading to a higher propensity to heart failure after MI. Currently, in vivo signaling studies are being carried out to understand molecular mechanisms by which NOX2-derived ROS in ECs result in impaired cardiac function.