Ca²⁺/calmodulin-dependent Kinase ? Regulates AMP-activated Protein Kinase Pathway And Targets Fatty Acid Metabolism In Ischemic Heart Disease

Rationale:Inhibition of Ca2+/calmodulin-dependent protein II(CaMKII)improves the cardiac function of patients with myocardial infarction(MI).However,the mechanism is incompletely understood.Objective:Here,we explore the role of CaMKII-dependent pathway in regulating myocardial fatty acid(FA)metabolism.Methods and Results:We examined the expression of key proteins related to CaMKII and FA metabolism in the heart of patients with terminal ischemic heart disease using western blot.These patients displayed increased phosphorylation of CaMKII and a series key proteins changes relating to FA metabolism,including increased AMP-activated protein kinase(AMPK),acetyl Co A carboxylase(ACC)and malonyl CoA decarboxylase(MCD).Then,we demonstrated that mice with genetic myocardial CaMKII inhibition(AC3-I)showed significant changes of a cluster of FA metabolism genes induced by myocardial infarction(MI),including AMPK.Importantly,post-MI AC3-I hearts exhibited reduced phosphorylation of AMPK and acetyl CoA carboxylase,and protein expression of MCD and FA translocase cluster of differentiation 36(FAT/CD36).Next,we demonstrated the direct association between cardiac CaMKII and AMPK by co-immunoprecipitation and GST Pull-down.GST Pull Down showed that 1-394 residues interacted CaMKII more strongly than any other fragments in AMPK ?1 subunit.While in AMPK a2 subunit,we found that 398-552 residues had more interaction with CaMKII.Conclusions:These novel findings provide both molecular and in vivo evidences for CaMKII in regulating FA metabolism in ischemic heart disease.