Abstract 442: Metformin Mitigates the Apoptosis Pathway in Ischemic Myocardium

Abstract

OBJECTIVE: Epidemiologic data has shown that metformin confers a survival advantage in patients with cardiovascular disease. Although the underlying cardioprotective mechanism is unclear, it appears to be independent of metformin’s insulin-sensitizing effect. The purpose of this study is to evaluate the effect of metformin on the apoptosis pathway in the ischemic cardiac tissue in a swine model of metabolic syndrome. METHODS: Ossabaw miniswine were fed either a regular diet (OC, n=8), or a high-cholesterol diet (OHC, n=9) or a high-cholesterol diet supplemented with metformin (OHCM n=8). After three weeks, all animals underwent placement of an ameroid constrictor to the left circumflex coronary artery to induce chronic ischemia. Seven weeks after ameroid placement, animals underwent cardiac harvest. RESULTS: Western blot analysis of protein expression in the ischemic territory is reported as fold change ± standard error of the mean (FC ± SEM) with respect to OC. See table. FoxO3a is a pro-apoptotic protein that is inactivated with phosphorylation. Caspase 3 is a pro-apoptotic protein that is activated only when cleaved. P38 and ERK1/2 are activated when phosphorylated and are involved in the apoptosis/survival pathway. CONCLUSIONS: Meformin selectively alters the apoptosis pathway by inhibiting FoxO3 and decreasing the active form of caspase 3, cleaved caspase 3. Metformin also up-regulates mitogen-activated kinase proteins p38 and ERK1/2, which are considered cardioprotective during ischemic preconditioning. Perhaps the altered activation of the apoptosis pathway in ischemic myocardium is one mechanism by which metformin is cardioprotective.