Malonyl CoA Decarboxylase Inhibition Improves Cardiac Function Post-Myocardial Infarction

Wei Wang; Liyan Zhang; Pavan K Battiprolu; Arata Fukushima; Khanh Nguyen; Kenneth Milner; Abhishek Gupta; Tariq Altamimi; Nikole Byrne; Jun Mori; Osama Abo Alrob; Cory Wagg; Natasha Fillmore; Shao-Hua Wang; Dongming M Liu; Angela Fu; Jenny Yinglin Lu; Mary Chaves; Alykhan Motani; John R Ussher; Jeff D Reagan; Jason R B Dyck; Gary D Lopaschuk

doi:10.1016/j.jacbts.2019.02.003

Malonyl CoA Decarboxylase Inhibition Improves Cardiac Function Post-Myocardial Infarction

JACC Basic Transl Sci. 2019 Jun 24;4(3):385-400. doi: 10.1016/j.jacbts.2019.02.003. eCollection 2019 Jun.

Authors

Wei Wang^{1

2}, Liyan Zhang¹, Pavan K Battiprolu³, Arata Fukushima¹, Khanh Nguyen³, Kenneth Milner¹, Abhishek Gupta¹, Tariq Altamimi¹, Nikole Byrne¹, Jun Mori¹, Osama Abo Alrob¹, Cory Wagg¹, Natasha Fillmore¹, Shao-Hua Wang², Dongming M Liu³, Angela Fu³, Jenny Yinglin Lu³, Mary Chaves³, Alykhan Motani³, John R Ussher⁴, Jeff D Reagan³, Jason R B Dyck¹, Gary D Lopaschuk¹

Affiliations

¹ Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
² Department of Cardiac Surgery, University of Alberta, Edmonton, Alberta, Canada.
³ Amgen, San Francisco, California.
⁴ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.

Abstract

Alterations in cardiac energy metabolism after a myocardial infarction contribute to the severity of heart failure (HF). Although fatty acid oxidation can be impaired in HF, it is unclear if stimulating fatty acid oxidation is a desirable approach to treat HF. Both immediate and chronic malonyl coenzyme A decarboxylase inhibition, which decreases fatty acid oxidation, improved cardiac function through enhancing cardiac efficiency in a post-myocardial infarction rat that underwent permanent left anterior descending coronary artery ligation. The beneficial effects of MCD inhibition were attributed to a decrease in proton production due to an improved coupling between glycolysis and glucose oxidation.

Keywords: ATGL, adipose triglyceride lipase; CPT1, carnitine palmitoyltransferase 1; EF, ejection fraction; FOXO3, forkhead box O3; MCD, malonyl coenzyme A decarboxylase; MI, myocardial infarction; SERCA2, sarco(endo)plasmic reticulum Ca2+-ATPase 2; SOD, superoxide dismutase; SPT, serine palmitoyltransferase; TAG, triacylglycerol; Trx, thioredoxin; fatty acid oxidation; glucose oxidation; heart failure; uncoupling of glycolysis.