Cardiac CaMKIIδ and Wenxin Keli Prevents Ang II-Induced Cardiomyocyte Hypertrophy by Modulating CnA-NFATc4 and Inflammatory Signaling Pathways in H9c2 Cells.

Na An,Xiandu Pan,Yonghong Gao,Yuanyuan Li,Ke Song,Xinye Li,Xiongyi Gao,Yang Li,Xin Wang,Hengwen Chen,Yu Chen,Fan Yang,Yanwei Xing,Yanfen Xing,Xiaofang He,Honghua Wu,Hong Chang

doi:10.1155/2020/9502651

Abstract

Previous studies have demonstrated that calcium-/calmodulin-dependent protein kinase II (CaMKII) and calcineurin A-nuclear factor of activated T-cell (CnA-NFAT) signaling pathways play key roles in cardiac hypertrophy (CH). However, the interaction between CaMKII and CnA-NFAT signaling remains unclear. H9c2 cells were cultured and treated with angiotensin II (Ang II) with or without silenced CaMKIIδ (siCaMKII) and cyclosporine A (CsA, a calcineurin inhibitor) and subsequently treated with Wenxin Keli (WXKL). Patch clamp recording was conducted to assess L-type Ca2+ current (ICa-L), and the expression of proteins involved in signaling pathways was measured by western blotting. Myocardial cytoskeletal protein and nuclear translocation of target proteins were assessed by immunofluorescence. The results indicated that siCaMKII suppressed Ang II-induced CH, as evidenced by reduced cell surface area and ICa-L. Notably, siCaMKII inhibited Ang II-induced activation of CnA and NFATc4 nuclear transfer. Inflammatory signaling was inhibited by siCaMKII and WXKL. Interestingly, CsA inhibited CnA-NFAT pathway expression but activated CaMKII signaling. In conclusion, siCaMKII may improve CH, possibly by blocking CnA-NFAT and MyD88 signaling, and WXKL has a similar effect. These data suggest that inhibiting CaMKII, but not CnA, may be a promising approach to attenuate CH and arrhythmia progression.

Highlights

Cardiomyocyte hypertrophy (CH) is an adaptive response to the pathological stimuli that maintain normal cardiac function
We explored the interaction between calmodulin-dependent protein kinase II (CaMKII) and CnANFAT signaling in CH induced by angiotensin II (Ang II) and the effect of Wenxin Keli (WXKL). erefore, we sought to characterize the role of CaMKII and CnA-nuclear factor of activated T cells (NFAT) signaling in cardiomyocytes using siRNA-mediated silencing and CsA
We analyzed the results of cytoskeletal enlargement; L-type Ca2+ current (ICa-L); expression of CaMKII, CnA-NFAT, and inflammatory signaling pathways in cardiomyocytes induced by Ang II; and the protein expression and nuclear transfer of NFATc4

Summary

Introduction

Cardiomyocyte hypertrophy (CH) is an adaptive response to the pathological stimuli that maintain normal cardiac function. The initially adaptive response can maintain cardiac output, sustained hypertrophic growth can lead to a pathological state that leads to decreased compliance, HF, and sudden death [1,2,3,4,5]. Different signaling molecules have been considered as causes of myocardial hypertrophy, including nuclear factor of activated T cells (NFAT), calcium-/calmodulin- (CaM-) dependent protein kinase II (CaMKII), and β-adrenergic receptors [6]. It is generally known that CaN plays an influential role in regulating pathological hypertrophy. It is known that CaMKII phosphorylates many vital signaling factors that are related to initiating abnormal hypertrophy [13]. The interaction between CaMKII and CnA-NFAT signaling for CH remains unclear

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Conclusion