双羟基黄酮醇抑制心衰后CaMKⅡ磷酸化降低室性心律失常易感性

3′,4′-Dihydroxyflavonol reduces susceptibility to ventricular arrhythmias by inhibiting CaMKⅡ phosphorylation after heart failure

目的:研究双羟基黄酮醇(DiOHF)通过抑制心衰(HF)后钙/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)的磷酸化水平来降低心衰后室性心律失常的易感性。方法:采用主动脉缩窄术(TAC)构建压力负荷性心衰小鼠模型,用小动物超声机确认模型构建成功。假手术组小鼠分为Control组和Control+DiOHF组,心衰小鼠分为HF组和HF+DiOHF组。采用心内程序性电刺激(PES)分别检测4组小鼠的心室起搏阈值和心室不应期,诱导室性心律失常并进行心律失常评分。采用Western Blot分析各组心脏蛋白中的CaMKⅡ及其磷酸化水平。结果:与Control组相比,HF组小鼠的心室起搏阈值减小,不应期缩短,室性心律失常评分显著增高。而HF+DiOHF组相比HF组起搏阈值增大,心室不应期增长,室性心律失常评分显著降低。同时Western Blot显示HF组相比Control组,CaMKⅡ磷酸化水平显著升高,而HF+DiOHF组CaMKⅡ磷酸化水平相比HF组明显下降。结论:CaMKⅡ的过度激活引起心衰后的室性心律失常,而DiOHF可通过抑制心衰后CaMKⅡ的磷酸化水平来减少室性心律失常。

Objective:To study the role of 3’,4’-dihydroxyflavonol(DiOHF)in reducing the susceptibility to ventricular arrhythmias by inhibiting the phosphorylation level of CaMKⅡafter heart failure(HF).Methods:Mice models of pressure-loaded heart failure were constructed by transverse aortic constric-tion(TAC).Confirming the successful construction of the model with a small animal ultrasound ma-chine.The sham-operated mice and heart failure mice were divided into control group,control+DiO-HF group,HF group and HF+DiOHF group.The ventricular pacing threshold and ventricular re-fractory period of each group were detected by intracardiac programmed electrical stimulation,respec-tively,ventricular arrhythmia was induced and arrhythmia score was performed.Results:Compared with the control group,in the HF group,the ventricular pacing threshold was reduced,the refractory period was shortened,and the ventricular arrhythmia scores were significantly increased.Compared with the HF group,the HF+DiOHF group increased the pacing threshold,the ventricular refractory period increased,and the ventricular arrhythmia score decreased significantly.Meanwhile,Western Blot showed that the phosphorylation level of CaMKⅡwas significantly increased in the HF group as compared with the control group,while the phosphorylation level of CaMKⅡin the HF+DiOHF group was significantly lower than that in the HF group.Conclusion:Excessive activation of CaMKⅡcan cause ventricular arrhythmias after heart failure,and DiOHF can reduce ventricular arrhyth-mias by inhibiting the phosphorylation level of CaMKⅡafter HF.