Abstract 14338: Mitochondria-Targeted ROS Scavenger JP4-039 Induces Coronary Angiogenesis in Ischemic Myocardium Resulting in the Improvement of Cardiac Function in Post-MI Animals

Abstract

Introduction: A reduction of mitochondrial reactive oxygen species (mito-ROS) has been sought as a potential approach for recovering energy supply and improving cardiac function in cardiovascular disease. Here, we evaluated JP4-039, a mito-ROS scavenger, for post-myocardial infarction (MI) recovery. Hypothesis: We hypothesized that mitochondrial antioxidant JP4-039 will induce coronary angiogenesis and improve post-MI cardiac function in mice. Methods: FVB mice (n=8/group) underwent MI surgery and were assigned to either vehicle (sunflower seed oil) or JP4-039 group (1mg/kg, i.p., 3x/week for 4 weeks). A SHAM surgery group received vehicle only. Left ventricle (LV) ejection fraction (EF), fractional shortening (FS), and fractional area change (FAC) were assessed by echocardiography 28 days post-MI. Capillary (CD31 antibody) and arteriole density (α-SMA antibody) were quantified by immunofluorescence of ischemic heart sections 28 days post-MI. Western blot of myocardial homogenates was conducted to evaluate activation of Akt, ERK1/2, and AMPKα. Data were analyzed by One-way ANOVA and Tukey’s post-hoc, and a p value <0.05 was taken as significant. Results: Mice treated with JP4-039 presented with a 35% decrease in infarction size, and a 57% increase in EF compared to the vehicle group (43.6±5.1 vs. 27.8±5.3). FS and FAC of JP4-039-treated mice increased by 65% (21.9±2.9 vs. 13.3±2.6) and 90% (38.0±5.6 vs. 20.0±4.0), respectively. In ischemic myocardium, the JP4-039 group showed an increase in capillary density of 39% in comparison to vehicle (208.6±21.7 vs 149.9±18.0). Interestingly, arteriogenesis was decreased in ischemic myocardium by 31% in JP4-039-treated mice compared to vehicle group (9.0±1.1 vs. 13.1±1.5). Although activation of Akt or ERK1/2 signaling were unchanged, p-AMPKα was decreased by 67% in JP4-039 vs. vehicle (0.39±0.07 vs. 0.65±0.03) in myocardium. Conclusions: The findings suggest that mitochondrial antioxidant JP4-039 improves capillary angiogenesis in ischemic myocardium, resulting in improved cardiac function in post-MI mice. Mechanisms involved in differential levels of capillary and arteriole densities in ischemic myocardium are being examined in human coronary ECs and will be presented at the meeting.