Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation

Abstract

Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid oxidation rates and an increase in glucose oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased glucose oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, glucose oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid oxidation and accelerate glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

“…7 Pharmacological MCD inhibition increases intracellular malonyl CoA levels, decreases fatty acid oxidation, and accelerates glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. 7 In addition, this switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD is a novel approach to treating ischemic heart disease.…”

“…7 Pharmacological MCD inhibition increases intracellular malonyl CoA levels, decreases fatty acid oxidation, and accelerates glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. 7 In addition, this switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD is a novel approach to treating ischemic heart disease. 7 Although the short-term regulation of MCD with the use of MCD inhibitors has shown promise for switching energy substrate preference and preventing ischemia/reperfusion injury, the effects of long-term inhibition of cardiac MCD on energy metabolism and ischemia/reperfusion injury are unknown.…”

“…7 In addition, this switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD is a novel approach to treating ischemic heart disease. 7 Although the short-term regulation of MCD with the use of MCD inhibitors has shown promise for switching energy substrate preference and preventing ischemia/reperfusion injury, the effects of long-term inhibition of cardiac MCD on energy metabolism and ischemia/reperfusion injury are unknown. Similarly, the effects of long-term systemic in vivo inhibition of MCD are also unknown.…”

“…16 Extraction of CoA esters and the measurement of malonyl CoA levels were performed as previously described. 7 Quantitative Reverse Transcriptase-Polymerase Chain Reaction Analysis RNA extraction and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of samples were performed by previously described methods. 17 Specific quantitative assays were designed from mouse sequences available in GenBank.…”

“…1 Alterations in intracellular malonyl CoA levels have also been implicated in the regulation of a number of physiological and pathological processes, which include the following: (1) feeding behavior 2 ; (2) hepatocyte-mediated whole-body insulin resistance 3 ; (3) whole-body energy expenditure and subsequent storage of fat in adipose tissue 4 ; (4) pancreatic beta cell insulin secretion 5 ; (5) skeletal muscle-mediated insulin resistance and type 2 diabetes 6 ; and (6) cardiac ischemia/reperfusion injury. 7 …”