Li Xinran, Hu Hesheng, Wang Ye, Xue Mei, Li Xiaolu, Cheng Wenjuan, Xuan Yongli, Yin Jie, Yang Na, Yan Suhua
*Shandong University, School of Medicine, Ji'nan, Shandong, China; and†Department of Cardiology, Qianfoshan Hospital of Shandong Province, Ji'nan, Shandong, China.
J Cardiovasc Pharmacol. 2016 Mar;67(3):252-9. doi: 10.1097/FJC.0000000000000341.
Myocardial infarction (MI) results in decreased inward-rectifier K⁺ current (IK1), which is mediated primarily by the Kir2.1 protein and is accompanied by upregulated T cells. Interferon γ (IFN-γ), secreted predominantly by Th1 cells, causes a decrease in IK1 in microglia. Whether Th1 cells can induce IK1/Kir2.1 remodeling following MI and whether valsartan can ameliorate this phenomenon remain unclear.
Rats experiencing MI received either valsartan or saline for 7 days. Th1-enriched lymphocytes and myocytes were cocultured with or without valsartan treatment. Th1 cells were monitored by flow cytometry. The protein levels of Kir2.1 were detected by Western blot analyses. IK1 was recorded through whole-cell patch clamping. The plasma levels of IFN-γ, interleukin 2, and tumor necrosis factor α were detected by enzyme-linked immunosorbent assay.
Th1 cell number and cytokine expression levels were higher following MI, and the Kir2.1 protein level was decreased. In MI rats, valsartan reduced Th1 cell number and cytokine expression levels and increased the Kir2.1 expression and the IK1 current compared with the rats that received saline treatment; these results are consistent with the effect of valsartan in cocultured lymphocytes and myocytes. In vitro, IFN-γ overexpression suppressed the IK1 current, whereas interleukin 2 and tumor necrosis factor α had no significant effect on the current, establishing that Th1 cell regulation of IK1/Kir2.1 expression is mainly dependent on IFN-γ.
Valsartan ameliorates IK1/Kir2.1 remodeling by downregulating the Th1 immune response following MI.
心肌梗死（MI）导致内向整流钾电流（IK1）降低，该电流主要由Kir2.1蛋白介导，并伴有T细胞上调。主要由Th1细胞分泌的干扰素γ（IFN-γ）可导致小胶质细胞中IK1降低。MI后Th1细胞是否能诱导IK1/Kir2.1重塑以及缬沙坦是否能改善这种现象尚不清楚。
经历MI的大鼠接受缬沙坦或生理盐水治疗7天。将富含Th1的淋巴细胞和心肌细胞进行共培养，有无缬沙坦处理。通过流式细胞术监测Th1细胞。通过蛋白质印迹分析检测Kir2.1的蛋白水平。通过全细胞膜片钳记录IK1。通过酶联免疫吸附测定法检测血浆中IFN-γ、白细胞介素2和肿瘤坏死因子α的水平。
MI后Th1细胞数量和细胞因子表达水平更高，而Kir2.1蛋白水平降低。在MI大鼠中，与接受生理盐水治疗的大鼠相比，缬沙坦降低了Th1细胞数量和细胞因子表达水平，并增加了Kir2.1表达和IK1电流；这些结果与缬沙坦在共培养的淋巴细胞和心肌细胞中的作用一致。在体外，IFN-γ过表达抑制了IK1电流，而白细胞介素2和肿瘤坏死因子α对该电流无显著影响，表明Th1细胞对IK1/Kir2.1表达的调节主要依赖于IFN-γ。
缬沙坦通过下调MI后的Th1免疫反应改善IK1/Kir2.1重塑。
