Li Xinran, Hu Hesheng, Wang Ye, Xue Mei, Li Xiaolu, Cheng Wenjuan, Xuan Yongli, Yin Jie, Yang Na, Yan Suhua
School of Medicine, Shandong University, Ji'nan, Shandong, China.
Cardiovasc Drugs Ther. 2015 Jun;29(3):209-18. doi: 10.1007/s10557-015-6598-1.
Myocardial infarction (MI) results in an increased susceptibility to ventricular arrhythmias, due in part to decreased inward-rectifier K+ current (IK1), which is mediated primarily by the Kir2.1 protein. The use of renin-angiotensin-aldosterone system antagonists is associated with a reduced incidence of ventricular arrhythmias. Casein kinase 2 (CK2) binds and phosphorylates SP1, a transcription factor of KCNJ2 that encodes Kir2.1. Whether valsartan represses CK2 activation to ameliorate IK1 remodeling following MI remains unclear.
Wistar rats suffering from MI received either valsartan or saline for 7 days. The protein levels of CK2 and Kir2.1 were each detected via a Western blot analysis. The mRNA levels of CK2 and Kir2.1 were each examined via quantitative real-time PCR.
CK2 expression was higher at the infarct border; and was accompanied by a depressed IK1/Kir2.1 protein level. Additionally, CK2 overexpression suppressed KCNJ2/Kir2.1 expression. By contrast, CK2 inhibition enhanced KCNJ2/Kir2.1 expression, establishing that CK2 regulates KCNJ2 expression. Among the rats suffering from MI, valsartan reduced CK2 expression and increased Kir2.1 expression compared with the rats that received saline treatment. In vitro, hypoxia increased CK2 expression and valsartan inhibited CK2 expression. The over-expression of CK2 in cells treated with valsartan abrogated its beneficial effect on KCNJ2/Kir2.1.
AT1 receptor antagonist valsartan reduces CK2 activation, increases Kir2.1 expression and thereby ameliorates IK1 remodeling after MI in the rat model.
心肌梗死（MI）会导致室性心律失常易感性增加，部分原因是内向整流钾电流（IK1）降低，而该电流主要由Kir2.1蛋白介导。使用肾素 - 血管紧张素 - 醛固酮系统拮抗剂与室性心律失常发生率降低相关。酪蛋白激酶2（CK2）结合并磷酸化SP1，SP1是编码Kir2.1的KCNJ2的转录因子。缬沙坦是否通过抑制CK2激活来改善MI后的IK1重塑尚不清楚。
患有MI的Wistar大鼠接受缬沙坦或生理盐水治疗7天。通过蛋白质印迹分析分别检测CK2和Kir2.1的蛋白水平。通过定量实时PCR分别检测CK2和Kir2.1的mRNA水平。
梗死边缘的CK2表达较高，同时IK1/Kir2.1蛋白水平降低。此外，CK2过表达抑制KCNJ2/Kir2.1表达。相反，CK2抑制增强KCNJ2/Kir2.1表达，表明CK2调节KCNJ2表达。在患有MI的大鼠中，与接受生理盐水治疗的大鼠相比，缬沙坦降低了CK2表达并增加了Kir2.1表达。在体外，缺氧增加CK2表达，缬沙坦抑制CK2表达。在缬沙坦处理的细胞中CK2的过表达消除了其对KCNJ2/Kir2.1的有益作用。
在大鼠模型中，AT1受体拮抗剂缬沙坦降低CK2激活，增加Kir2.1表达，从而改善MI后的IK1重塑。
