阿托伐他汀对早期慢性肾脏病颈动脉斑块患者周围淋巴细胞GSK-3的作用

Effects of Atorvastatin on glycogen synthase kinase-3 in lymphocytes of carotid atherosclerotic plaques in patients with early chronic kidney disease

目的探讨阿托伐他汀对早期慢性肾脏病(CKD)颈动脉斑块患者周围血淋巴细胞糖原合酶激酶-3(GSK-3)的作用。方法选择2017年1~10月在上海健康医学院附属第六人民医院东院和山东省菏泽市立医院就诊的CKD 1~2期并颈动脉斑块患者143例,按照随机数字表法将其分为CKD组(76例)和治疗组(67例)。同时选择同期年龄在42岁以上的正常人50名为对照组。治疗组口服阿托伐他汀20 mg/晚,治疗6个月后观察不同时间点患者外周血淋巴细胞GSK-3β活性及GSK-3βSer9位点的磷酸化水平变化。采用放射性配体结合试验检测GSK-3β的活性,蛋白质印迹法检测GSK-3βSer9位点的磷酸化及总GSK-3β水平。结果治疗前,与对照组比较,CKD组颈动脉内膜中层厚度(IMT)明显增厚(P <0.01),外周血淋巴细胞GSK-3β的活性明显降低(P <0.01),且外周血淋巴细胞GSK-3βSer9位点的磷酸化水平明显升高(P <0.01)。与CKD组比较,治疗组使用阿托伐他汀治疗6个月可使IMT缩小(P <0.05),促进GSK-3β的活性明显恢复(P <0.01),且能降低外周血淋巴细胞GSK-3βSer9位点的磷酸化水平(P <0.01)。结论本研究提示CKD患者外周淋巴细胞GSK-3活性降低可能与促进颈动脉粥样硬化及斑块形成有关,并进一步提示阿托伐他汀可能通过降低GSK-3βSer9位点的磷酸化水平,升高GSK-3活性,从而进一步抑制颈动脉硬化及斑块的形成。

Objective To explore the effects of Atorvastatin on glycogen synthase kinase-3(GSK-3) in lymphocytes of carotid plaques in patients with early chronic kidney disease(CKD). Methods One hundred and forty-three patients with CKD 1-2 and carotid plaque from January to October 2017 in East Branch of Shanghai Sixth People′s Hospital Affiliated to Shanghai University of Medicine & Health Sciences and Heze Municipal Hospital were enrolled and divided into CKD group(76 cases) and treatment group(67 cases) according to random number table method. At the same time, 50 normal people over the age of 42 years were selected as the control group. The treatment group received oral Atorvastatin 20 mg/night. After 6 months of treatment,the activity and expression changes of GSK-3β and GSK-3β at Ser9 in peripheral blood lymphocytes of patients at different time points were observed. The GSK-3 activity was measured by 32 P liquid scintillography for incorporated radioactivity, and the phosphorylation of GSK-3β at Ser9 and the total GSK-3β were determined by Western blot. Results Before treatment, compared with the control group, the carotid intima-media thickness(IMT) was significantly thicker(P < 0.01), and the activity of GSK-3β was significantly decreased(P < 0.01), and the phosphorylation of GSK-3β at Ser9 was significantly increased in lymphocytes in CKD group(P < 0.01). When the treatment group treated with Atorvastatin for 6 months,the thickened IMT was reversed(P < 0.05), and the activity of GSK-3 was resumed(P < 0.01), and the phosphorylation of GSK-3β at Ser9 was decreased as compared with CKD group(P < 0.01). Conclusion Lower activities of GSK-3 in lymphocytes of patients with early CKD might be associated with the formation and promotion of carotid atherosclerosis plaque. Atorvastatin might inhibit carotid atherosclerotic plaques by increasing activity of GSK-3 in phosphorylation of GSK-3β at Ser9.