Ca2+/calmodulin-dependent protein kinase II inhibition reduces myocardial fatty acid uptake and oxidation after myocardial infarction

• Published in: Biochimica et biophysica acta. Molecular and cell biology of lipids 2022-06, Vol.1867 (6), p.159120-159120, Article 159120
• Main Authors: Meng, Yidi, Ding, Peiwu, Wang, Hongfei, Yang, Xueke, Wang, Zhiyu, Nie, Daan, Liu, Jie, Huang, Yun, Su, Guanhua, Hu, Jun, Su, Yanwen, Du, Xinling, Dong, Nianguo, Jia, Haibo, Zhang, Hongbing, Zhang, Jiaming, Li, Jingdong
• Format: Article
• Language: English
• Subjects: Acetyl-CoA carboxylase (ACC); AMP-activated kinase (AMPK); Ca2+/calmodulin-dependent protein kinase II (CaMKII); FA translocase cluster of differentiation 36 (FAT/CD36); Fatty acid metabolism; Ischemic heart disease
• ISSN: 1388-1981; 1879-2618
• DOI: 10.1016/j.bbalip.2022.159120

An AMP-activated kinase (AMPK) signaling pathway is activated during myocardial ischemia and promotes cardiac fatty acid (FA) uptake and oxidation. Similarly, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also triggered by myocardial ischemia, but its function in FA metabolism remains unclear. Here, we explored the role of CaMKII in FA metabolism during myocardial ischemia by investigating the effects of cardiac CaMKII on AMPK-acetyl-CoA carboxylase (ACC), malonyl CoA decarboxylase (MCD), and FA translocase cluster of differentiation 36 (FAT/CD36), as well as cardiac FA uptake and oxidation. Moreover, we tested whether CaMKII and AMPK are binding partners. We demonstrated that diseased hearts from patients with terminal ischemic heart disease displayed increased phosphorylation of CaMKII, AMPK, and ACC and increased expression of MCD and FAT/CD36. AC3-I mice, which have a genetic myocardial inhibition of CaMKII, had reduced gene expression of cardiac AMPK. In post-MI (myocardial infarction) AC3-I hearts, AMPK-ACC phosphorylation, MCD and FAT/CD36 levels, cardiac FA uptake, and FA oxidation were significantly decreased. Notably, we demonstrated that CaMKII interacted with AMPK α1 and α2 subunits in the heart. Additionally, AC3-I mice displayed significantly less cardiac hypertrophy and apoptosis 2 weeks post-MI. Overall, these findings reveal a unique role for CaMKII inhibition in repressing FA metabolism by interacting with AMPK signaling pathways, which may represent a novel mechanism in ischemic heart disease. •CaMKII modulates a series of fatty acid metabolism-related genes following MI.•Cardiac CaMKII inhibition reduces fatty acid uptake and oxidation.•A direct interaction between CaMKII and AMPK is found in the heart.•Cardiac CaMKII inhibition down-regulates AMPK-ACC signaling after MI.