Abstract 14479: Prolonged Decrease in Endothelial Cell (EC)-Specific Mitochondrial ROS Results in Mitochondrial Dysfunction in Coronary EC and Cardiac Hypertrophy in Post-AMI Animals

Abstract

Introduction: Reducing mitochondrial ROS (mito-ROS) has been a novel approach for improving cardiac function. Here, we evaluated the effect of prolonged decrease in EC-specific mito-ROS on post-acute myocardial infarction (AMI) coronary angiogenesis and cardiac function. Hypothesis: We hypothesized that a prolonged decrease in EC-specific mito-ROS contributes to mitochondrial dysfunction in coronary EC resulting in post-AMI maladaptive cardiac remodeling. Methods: We used an EC-specific, tetracycline-controlled, transgenic MnSOD overexpression (MnSOD-OE) model. After 16 weeks of MnSOD-OE, mice underwent ligation of left anterior coronary artery (AMI). 28 days post-AMI, ejection fraction (EF), fractional shortening (FS), and left ventricle (LV) mass were determined by echocardiography (n=8/group). Isolated mouse heart ECs (MHEC) were evaluated by Seahorse for mitochondrial function and by western blot for cell signaling. Data were analyzed by Student’s t test. A p -value ≤0.05 was considered statistically significant. Results: MnSOD-OE mice showed 33% decrease (44.4±2.3 vs. 29.7±3.5) in EF and 35% decrease (21.7±1.2 vs. 14.2±1.7) in FS, compared to control. LV mass was increased by 51% (76.4±1.8 vs. 115.1±12.33 mg) in MnSOD-OE heart. LV end systolic and diastolic areas were increased in MnSOD-OE, by 2-fold (5.8±0.4 vs. 12.6±1.8) and 1.7-fold (9.8±0.5 vs. 16.8±1.6 mm 2 ), respectively. MnSOD-OE MHEC showed a reduction in mitochondrial maximal and spare respiration capacities, and decreased activation of Akt by 25% and ERK by 23%. Conclusions: Prolonged MnSOD-OE impaired mitochondrial respiration and inhibited Akt and ERK signaling in MHEC. These changes were associated with maladaptive remodeling post-AMI, including cardiac hypertrophy, LV dilatation, and systolic dysfunction. Together, these findings suggest that prolonged decrease in mito-ROS has detrimental effects on coronary EC resulting in maladaptive post-AMI cardiac remodeling.