Ca2+/calmodulin-dependent protein kinase II inhibition reduces myocardial fatty acid uptake and oxidation after myocardial infarction
Ca2+/calmodulin-dependent protein kinase II inhibition reduces myocardial fatty acid uptake and oxidation after myocardial infarction
复制标题
Ca2/钙调蛋白依赖性蛋白激酶 II 抑制可减少心肌梗死后心肌脂肪酸的摄取和氧化
DOI：
10.1016/j.bbalip.2022.159120
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发表时间：
2022-03-01
影响因子：
4.8
通讯作者：
Li, Jingdong
中科院分区：
文献类型：
--
作者：
Meng, Yidi;Ding, Peiwu;Li, Jingdong
AMP 激活激酶 (AMPK) 信号通路在心肌缺血期间被激活，促进心脏脂肪酸 (FA) 的摄取和氧化。同样，多功能Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）也由心肌缺血触发，但其在FA代谢中的功能仍不清楚。在这里，我们通过研究心脏 CaMKII 对 AMPK-乙酰辅酶 A 羧化酶 (ACC)、丙二酰辅酶 A 脱羧酶 (MCD) 和 FA 转位酶分化簇 36 (FAT/CD36) 以及心脏 FA 摄取和氧化的影响，探讨了 CaMKII 在心肌缺血期间 FA 代谢中的作用。此外，我们测试了 CaMKII 和 AMPK 是否是结合伙伴。我们证明，终末期缺血性心脏病患者的患病心脏表现出 CaMKII、AMPK 和 ACC 磷酸化增加，以及 MCD 和 FAT/CD36 表达增加。 AC3-I 小鼠具有 CaMKII 的遗传性心肌抑制作用，其心脏 AMPK 的基因表达降低。在 MI（心肌梗塞）后 AC3-I 心脏中，AMPK-ACC 磷酸化、MCD 和 FAT/CD36 水平、心脏 FA 摄取和 FA 氧化显着降低。值得注意的是，我们证明 CaMKII 与心脏中的 AMPK α 1 和 α 2 亚基相互作用。此外，MI 后 2 周，AC3-I 小鼠的心脏肥大和细胞凋亡明显减少。总的来说，这些发现揭示了 CaMKII 抑制通过与 AMPK 信号通路相互作用来抑制 FA 代谢的独特作用，这可能代表了缺血性心脏病的一种新机制。
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 alpha 1 and alpha 2 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.