Abstract：
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.
摘要：
AMP激活的激酶(AMPK)信号通路在心肌缺血期间被激活并促进心脏脂肪酸(FA)摄取和氧化。同样，多功能Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）也是由心肌缺血触发的，但其在FA代谢中的功能尚不清楚。这里,我们通过研究心脏CaMKII对AMPK-乙酰辅酶A羧化酶（ACC）的影响，探讨了CaMKII在心肌缺血时FA代谢中的作用，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的摄取和氧化。此外，我们检测了CaMKII和AMPK是否为结合伴侣.我们证明晚期缺血性心脏病患者的患病心脏显示CaMKII磷酸化增加，AMPK,和ACC以及MCD和FAT/CD36的表达增加。AC3-I小鼠,对CaMKII有遗传性心肌抑制作用，心脏AMPK基因表达降低。在MI后（心肌梗死）AC3-I心脏中，AMPK-ACC磷酸化，MCD和FAT/CD36水平，心脏FA摄取，和FA氧化显著降低。值得注意的是,我们证明CaMKII与心脏中的AMPKα1和α2亚基相互作用。此外,AC3-I小鼠在MI后2周表现出明显较少的心脏肥大和细胞凋亡。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。
