Abstract 5058: Glucose OxidationStimulation Affords Dramatic Protection Against in vivo Myocardial Ischemia Reperfusion Injury
During reperfusion of the ischemic myocardium, fatty acid oxidation rates quickly recover, while glucose oxidation rates remain low, which decreases cardiac efficiency during reperfusion. Malonyl CoA decarboxylase (MCD) degrades malonyl CoA and increases fatty acid oxidation by relieving malonyl CoA-dependent inhibition of carnitine palmitoyl transferase-1. Studies have shown that MCD inhibition improves reperfusion recovery of ischemic hearts ex vivo by reducing fatty acid oxidation rates and increasing glucose oxidation rates. The objective of this study was to determine whether MCD inhibition would translate into a reduction in infarct size. Wild Type (WT, n = 7) or MCD deficient (MCD−/−, n = 7) mice had their left anterior descending coronary artery ligated for 30 min followed by 24 hr reperfusion. MCD−/− mice demonstrated a dramatic reduction in infarct size compared to WT mice (10.8±3.8 vs. 39.5±4.7 % of area at risk, P < 0.05) despite similar areas at risk (53 vs. 52 % of left ventricle). Furthermore, malonyl CoA levels were higher in the area at risk of hearts from MCD−/− mice (3.9±0.7 vs. 1.9±0.5 nmol/g wet weight, P < 0.05). Because the protection against ex vivo ischemia/reperfusion injury in MCD−/− mice was associated with increased myocardial glucose oxidation rates, secondary to an inhibition of fatty acid oxidation, we next determined whether direct stimulation of pyruvate dehydrogenase (PDH) and subsequent glucose oxidation would also afford protection against myocardial infarction. Infusion of the PDH activator, dichloroacetate (100 mg/kg intraperitoneal injection, followed by hourly injections of 50 mg/kg for the 24 hr duration of reperfusion), demonstrated significant protection against myocardial infarction (36.4±2.4 vs. 50.3±3.2 % of area at risk, P < 0.05). We demonstrate that MCD inhibition is beneficial against ischemia/reperfusion injury, possibly due to its effects on glucose oxidation stimulation, validating the optimization of myocardial metabolism as a novel therapy for ischemic heart disease.