Role of CaMKII in free fatty acid/hyperlipidemia-induced cardiac remodeling both in vitro and in vivo

- Cardiac CaMKII activation can be induced by free fatty acids (FFAs)/hyperlipidemia.
- CaMKII inhibition can prevent FFAs/hyperlipidemia-induced cardiac pathological remodeling.
- CaMKII is the node point for regulating multiple pathological events in FFAs/hyperlipidemia-induced cardiac remodeling.
- TLR4 may be the upstream signal of CaMKII in cardiac cells in response to FFAs/hyperlipidemia.

RationaleThe cellular mechanisms of obesity/hyperlipidemia-induced cardiac remodeling are many and not completely elucidated. Ca2 +/calmodulin-dependent protein kinase II (CaMKII), a multifunctional serine/threonine kinase, has been reported to be involved in a variety of cardiovascular diseases. However, its role in obesity/hyperlipidemia-induced cardiac remodeling is still unknown.ObjectiveThe objective of this study was to demonstrate the role of CaMKII in the pathogenesis of obesity/hyperlipidemia-induced cardiac remodeling both in vitro and in vivo.Methods and resultsIn cardiac-derived H9C2 cells, palmitate treatment induced cell apoptosis coupled with activation of the mitochondrial apoptotic pathway, and cell hypertrophic and fibrotic responses. All of these alterations were inhibited by pharmacological inhibition of CaMKII with either of two specific inhibitors, Myr-AIP and KN93. In addition, an increased inflammatory response coupled with activation of the MAPKs and NF-κB signaling pathway, exaggerated oxidative stress, ER stress and autophagy were also observed in palmitate-treated H9C2 cells, while pretreatment with CaMKII inhibitors decreased these pathological signals. Furthermore, we also demonstrated that TLR4 is upstream signal of CaMKII in palmitate-treated H9C2 cells. In APOE−/− mice fed a high-fat diet (HFD) for 16 weeks, serum lipid profiles (FFAs, TG, TC) and blood glucose levels were significantly increased compared with mice fed a normal diet. In addition, apparent cardiac hypertrophy, fibrosis and apoptosis associated with increased inflammation, ER stress, and autophagy were also observed in the hearts of HFD-fed mice. However, all these changes were reversed by 8-weeks of KN93 peritoneal injections. KN93 also increased antioxidant defense as evidenced by increased expression of the Nrf2 system in the hearts of HFD-fed mice.ConclusionsTaken together, our results demonstrate a critical role of CaMKII in the pathogenesis of obesity/hyperlipidemia-induced cardiac remodeling. Also, TLR4 may be an upstream signal of cardiac CaMKII under hyperlipidemia conditions. These results suggest that CaMKII has the potential to be a therapeutic target in the prevention of obesity/hyperlipidemia-induced cardiac remodeling.