Post-ischemic reperfused myocardium has impaired pyruvate oxidation, accelerated fatty acid oxidation, and decreased contractile work and mechanical efficiency. Diabetes exacerbates these responses to ischemia. Pyruvate is oxidized by pyruvate dehydrogenase (PDH) which is strongly inhibited by its product, acetyl CoA. Acetyl CoA is also the product of Beta-oxidation of fatty acids, thus fatty acid oxidation inhibits pyruvate oxidation. The rate of fatty acid oxidation in cardiomyocytes is primarily controlled by the activity of carnitine palmitoyl transferase I (CPT I). Pharmacological stimulation of PDH or inhibition of CPT-I increases pyruvate oxidation and improves contractile recovery from ischemia in normal and diabetic hearts. CPT-I is inhibited by malonyl CoA, which is synthesized in the cytosol by acetyl CoA carboxylase (ACC). Reperfused isolated rat hearts have low ACC activity and malonyl CoA content, suggesting that this mechanism is responsible for the high rate of fatty acid oxidation and inhibition of carbohydrate oxidation after ischemia. Insulin increases malonyl CoA content, and should result in improved contractile recovery in reperfused myocardium via greater inhibition of CPT-1 by malonyl CoA. The general hypothesis that will be tested in this grant is that the activity of PDH and the rate of pyruvate oxidation are regulated by the rate of fatty acid oxidation. More specifically, malonyl CoA controls the activity of CPT-1 and the rate of Beta-oxidation of fatty acids. Insulin stimulates pyruvate oxidation by activating ACC and raising the concentration of malonyl CoA, thus inhibiting CPT-I, decreasing the rate of fatty acid oxidation and removing acetyl CoA inhibition on PDH. Thus, insulin will improve contractile recovery post ischemia by increasing pyruvate via this mechanism.
Specific aims of this grant are to: 1) Determine if insulin-induced activation of PDH and pyruvate oxidation are due to activation of ACC and greater malonyl CoA inhibition of fatty acid oxidation. 2) Determine if impaired pyruvate oxidation during post-ischemic reperfusion is due to decreased ACC activity, low malonyl CoA concentration, and uninhibited fatty acid oxidation. 3) Determine if the impaired contractile function and pyruvate oxidation is post-ischemic reperfused myocardium is corrected by acute treatment with insulin in normal and streptozotocin diabetic swine.
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