Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate.
Acetoacetate, when present as the only fuel for respiration in rat hearts, causes an impairment in contractile function that is reversible with the addition of substrates that can contribute to anaplerosis. To determine the importance of pyruvate carboxylation via NADP(+)-dependent malic enzyme on metabolism and function in hearts oxidizing acetoacetate, isolated working rat hearts were perfused with [1-14C]pyruvate and acetoacetate. While the cardiac power output after 60 min of perfusion in hearts utilizing acetoacetate alone had fallen to 44% of the initial value, the addition of pyruvate resulted in a stable performance with no fall in the work output. When hydroxymalonate, an inhibitor of NADP(+)-dependent malic enzyme and malate dehydrogenase, was added to the two substrates, function at 60 min was similar to the value for hearts oxidizing acetoacetate alone. Measurements of the specific activities of malate, aspartate, and citrate confirm inhibition of both pyruvate carboxylation and malate oxidation. The findings are consistent with a mechanism in which the enrichment of malate by pyruvate improves function by increasing the production of reducing equivalents by the malate dehydrogenase and the isocitrate dehydrogenase reactions increase flux through the span of the tricarboxylic acid cycle from malate to 2-oxoglutarate. The present study demonstrates the physiological importance of anaplerotic pathways in maintaining contractile function in the heart.
Russell
R R
RR
Department of Medicine, University of Texas Medical School, Houston 77030.
Taegtmeyer
H
H
D000090:Acetoacetates / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D003065:Coenzyme A / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009249:NADP / Q000494:pharmacology; D010084:Oxidation-Reduction; D011773:Pyruvates / Q000378:metabolism*; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D013646:Tartronates / Q000494:pharmacology
D000090:Acetoacetates; D011773:Pyruvates; D013646:Tartronates; C032973:tartronic acid; C016635:acetoacetic acid; D009249:NADP; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D008291:Malate Dehydrogenase; D003065:Coenzyme A