Abstract 17000: Pre-Conditioning with an Apo-lipoprotein Mimetic Peptide Recruits Adiponectin Dependent p-AMPK and Prevents Ischemic Cardiac Injury

Abstract

Objectives: Heme-heme oxygenase (HO) system is one of the first line defenses against alterations in cellular redox, and, has been show to protect against vascular endothelial dysfunction in chronic diseased states, such as obesity and diabetes. We tested the hypothesis that pre-conditioning with L4F attenuates ischemia induced cardiac dysfunction in diabetic mice. Methods: db/db mice were treated with either L-4F (an apo-lipoprotein mimetic inducer of HO) or vehicle for 8 weeks. Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1beta, TNF-alpha, MCP-1) were measured in plasma so as to confirm a diabetic, inflammatory state. Trans-thoracic echocardiography was performed at the completion of the experiment after which, isolated hearts were subjected to ischemia/reperfusion (IR) while mounted on a Langendorff's preparation. Isolated hearts were then analyzed for HO-1, pAMPK, peNOS, iNOS, adiponectin and superoxide levels. Results: As shown before, db/db mice developed hyperglycemia with hyperinsulinemia and exhibited significantly increased (p<0.05) circulating levels of inflammatory cytokines including, TNFalpha, MCP-1 and IL1beta. Cardiac function was significantly compromised (p<0.05) in db/db mice with enhancement of coronary resistance (CR) and reduced LVDevp and reduced cardiac muscle shortening (dP/dT). L-4F treatment increased insulin sensitivity and adiponectin levels (p<0.05), while lowering inflammatory cytokines (p<0.05) in these mice. Also, L-4F normalized LV function by increasing (p<0.05) fractional shortening and decreasing (p<0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice (p<0.05). These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS and adiponectin and decreased levels of superoxide and iNOS (p<0.01). Conclusion: Attenuation of L-4F-induced myocardial and coronary functional abnormalities in db/db mice, involves HO induction and recruitment of adiponectin-dependent anti-inflammatory, anti-oxidative, and vasodilatory pathways; including activation of pAMPK and peNOS.