Abstract 14422: Mitochondrial ROS Scavenger JP4-039 Improves Mitochondrial Oxidative Phosphorylation and Induces Angiogenesis in Murine and Human Coronary Artery and Atrial Endothelial Cells

Abstract

Introduction: Reducing mitochondrial ROS (mito-ROS) has been a therapeutic goal to improve cardiovascular disease. Here, we evaluated the effects of mito-ROS scavenger JP4-039 with a focus on mouse heart and human coronary artery endothelial cell (MHEC, HCAEC). Hypothesis: We hypothesized that JP4-039 would improve oxidative phosphorylation (OXPHOS) in EC and induce angiogenesis in post-AMI (acute myocardial infarction) hearts. Methods: Human atrial explants, NOX2-overexpressing (OE) MHEC, and HCAEC were treated with 1-5μM JP4-039 and examined for sprouting, tube formation, mitochondrial complex expression (Western blot), and OXPHOS measurements (Seahorse). FVB mice (n=8/group) underwent AMI surgery and were assigned to vehicle (sunflower seed oil) or JP4-039 group (1mg/kg, i.p., 3x/week for 4 weeks). Left ventricle (LV) function and capillary density in infarcted LV were assessed by echocardiogram and immunofluorescence, respectively, 28 days after AMI. Data were analyzed by One-way ANOVA and Tukey’s post-hoc, or student’s t test, as appropriate. A p-value <0.05 was considered statistically significant. Results: HCAEC treated with JP4-039 showed significantly increased expression of mitochondrial complex I (0.7±0.1 vs. 1.1±0.1) and V (1.0±0.1 vs. 1.2±0.1) with corresponding increase in basal (19.8±0.4 vs. 23.0±1.0) and maximal respiration (31.2±1.6 vs. 56.0±2.6), ATP production (16.6±0.3 vs. 18.5±0.4) and spare respiratory capacity (11.3±1.6 vs. 33.0±2.9) as compared with vehicle-treated cells. JP4-039 increased tube formation in NOX2-OE MHEC (12.6±2.2 vs. 21.3±2.4 tubes), HCAEC (33.6±3.1 vs. 49.0±2.6) as well as EC sprouting in mouse atrium (4496±1857 vs. 19552±4352 pixel 2 ). In post-AMI animals, JP4-039 improved LV systolic function (EF 24.4±3.6 vs 41.3±5.2%) and capillary density (451.7 (379.9; 629.7) vs. 698.3 (503.6; 965.8) capillaries/mm 2 ) in vivo . Conclusions: JP4-039 improved OXPHOS in ECs in vitro, and induced coronary angiogenesis in post-AMI hearts in vivo and in atrial tissues ex vivo . These findings were associated with improved cardiac function in post-AMI animals, suggesting that a mito-ROS scavenger may have significant roles in coronary angiogenesis in ischemic myocardium.