Author + information
- Received November 13, 2018
- Revision received February 4, 2019
- Accepted February 11, 2019
- Published online June 24, 2019.
- Wei Wang, MD, PhDa,b,∗,
- Liyan Zhang, PhDa,∗,
- Pavan K. Battiprolu, PhDc,
- Arata Fukushima, MD, PhDa,
- Khanh Nguyen, BSc,
- Kenneth Milner, BSa,
- Abhishek Gupta, PhDa,
- Tariq Altamimi, PhDa,
- Nikole Byrne, BSa,
- Jun Mori, MD, PhDa,
- Osama Abo Alrob, PhDa,
- Cory Wagga,
- Natasha Fillmore, PhDa,
- Shao-hua Wang, MD, PhDb,
- Dongming M. Liu, BSc,
- Angela Fu, BSc,
- Jenny Yinglin Lu, BSc,
- Mary Chaves, MSc,
- Alykhan Motani, PhDc,
- John R. Ussher, PhDd,
- Jeff D. Reagan, PhDc,
- Jason R.B. Dyck, PhDa and
- Gary D. Lopaschuk, PhDa,∗ ()
- aCardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
- bDepartment of Cardiac Surgery, University of Alberta, Edmonton, Alberta, Canada
- cAmgen, San Francisco, California
- dFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
- ↵∗Address for correspondence:
Dr. Gary Lopaschuk, Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, 423 Heritage Medical Research Center, University of Alberta, Edmonton T6G 2S2, Canada.
• MCD inhibition decreases fatty acid oxidation via increasing malonyl coenzyme A levels to prevent fatty acid uptake into mitochondria in the failing hearts induced by coronary artery ligation.
• Downregulating fatty acid oxidation by MCD inhibition occurrs in conjuction with a decrease in glycolysis and in proton production while an increase in triacylglycerol biosynthesis.
• MCD inhibition enhances antioxidative capacity through increasing mitochondrial superoxide dismutase activity via reducing its acetylation.
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.
↵∗ Drs. Wang and Zhang contributed equally to this work and are joint first authors.
Drs. Nguyen, Fu, Motani, and Reagan are employees/shareholders of Amgen, Inc. Dr. Lupaschuk has received grants from the Canadian Institutes of Health Research; is an Alberta Heritage Foundation for Medical Research Medical Scientist; and is a shareholder in Metabolic Modulators Research Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and U.S. Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received November 13, 2018.
- Revision received February 4, 2019.
- Accepted February 11, 2019.
- 2019 The Authors