|Dyck, Jason - UNIV ALBERTA|
|Hopkins, Teresa - UNIV ALBERTA|
|Bonnet, Sebastien - UNIV ALBERTA|
|Michelakis, Evangelos - UNIV ALBERTA|
|Watanabe, Miho - CHUGAI RES INST|
|Kawase, Yosuke - CHUGAI RES INST|
|Jishage, Kou-Ichi - CHUGAI RES INST|
|Lopaschuk, Gary - UNIV ALBERTA|
Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 18, 2006
Publication Date: October 17, 2006
Citation: Dyck, J.R.B., Hopkins, T.A., Bonnet, S., Michelakis, E.D., Young, M.E., Wantanabe, M., Kawase, Y., Jishage, K., Lopaschuk, G.D. 2006. Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation. 114:1721-1728. Interpretive Summary: During a heart attack (myocardial infarction), the heart changes its preference in the fuel that it uses for energy, from fat to carbohydrate. However, blood fat levels increase after a heart attack, which counteracts this fuel switch. The question arises whether this fuel switch during a heart attack is beneficial or not. Inhibition of an enzyme call malonyl-CoA decarboxylase promotes this fuel switch, by blocking fat metabolism. This study shows that mice lacking malonyl-CoA decarboxylase have a better outcome following a simulated heart attack. These results suggest that drugs inhibiting fat metabolism may improve outcomes following a heart attack.
Technical Abstract: Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabolism, or ischemic cardioprotection. Mcd-deficient mice were produced and assessed for in vivo cardiac function as well as ex vivo cardiac function, energy metabolism, and ischemic tolerance. In vivo and ex vivo cardiac function was similar in wild-type and mcd-/- mice. Ex vivo working hearts from mcd-/- and wild-type mice displayed no significant differences in rates of fatty acid oxidation, glucose oxidation, or glycolysis. However, cardiac deletion of mcd resulted in an increased expression of genes regulating fatty acid utilization that may compensate for the loss of MCD protein and likely contributes to the absence of changes in energy metabolism in the aerobic heart. Despite the lack of changes in fatty acid utilization, hearts from mcd-/- mice displayed a marked preference for glucose utilization after ischemia, which correlated with a significant cardioprotection of ischemic hearts from mcd-/- mice compared with wild-type mice. Deletion of MCD markedly increases glucose oxidation and improves functional recovery of the heart after ischemia. As a result, chronic pharmacological inhibition of MCD may be a viable approach to treat myocardial ischemia.