钙离子/钙调素依赖性蛋白激酶Ⅱ在大鼠胚胎心肌肥大细胞中调控血管紧张素Ⅱ诱导的细胞自噬

Ca^(2+)/calmodulin-dependent protein kinase Ⅱ regulates cardiac hypertrophy by mediating autophagy

目的:探讨钙离子/钙调素依赖性蛋白激酶Ⅱ(Ca^(2+)/calmodulin-dependent protein kinase Ⅱ,CaMK Ⅱ)与细胞自噬在胚胎心肌细胞肥大发展过程中的相互作用。方法:使用血管紧张素Ⅱ作用于大鼠胚胎心肌细胞株H9c2细胞,建立体外心肌细胞肥大模型,通过药物抑制和基因过表达及敲除等方法分析细胞自噬通路AMPK-LC3 Ⅱ。结果:血管紧张素Ⅱ可快速诱导CaMKⅡ及细胞自噬相关通路AMPK磷酸化以及细胞自噬标记蛋白LC3 Ⅱ表达,CaMKⅡ抑制剂以及基因敲除和药物抑制CaMK Ⅱ下游因子组蛋白乙酰转移酶4(HDAC4)可显著阻断血管紧张素Ⅱ诱导的LC3 Ⅱ蛋白表达(P<0.05)。结论:CaMK Ⅱ作为心肌肥大病理过程的中心调控子,可以通过AMPK或其下游HDAC4直接或间接调控细胞自噬,进而调节心肌肥大的发生发展。

Objective To elucidate the relationship between Ca2+/calmodulin?dependent protein kinaseⅡ(CaMKⅡ)and autophagy during the development of cardiac hypertrophy.Methods Rat embryonic cardiac cellline H9c2cells was treated by angiotensinⅡto establish cardiomyocyte hypertrophy model in vitro and usingantagonists and gene function gain and loss to analyze AMPK?LC3Ⅱautophagy signaling pathway.Results Thephosphorylation of CaMKⅡand autophagy related signaling?AMPK and autophagy marker LC3Ⅱwere rapidlyincreased by angiotensinⅡtreatment at early stage.However,the above changes were highly blocked by CaMKⅡinhibitor and HDAC4inhibition.Conclusion CaMKⅡis the center factor of regulating cardiac hypertrophy,itmediates autophagy through directly regulating AMPK or indirectly regulating HDAC4during the development ofcardiac hypertrophy.