2022 年第 12 期 第 17 卷

沙库巴曲缬沙坦对自发性高血压大鼠心肌钙调神经磷酸酶/活化T细胞核因子3信号通路的影响

Effects of sacubitril/valsartan on cardiac calcineurin /nuclear factor of activated T cell3 signaling pathway in myocardium of spontaneously hypertensive rats

作者：马志兰1于欣2刘文杰3何静4杨震5

英文作者：Ma Zhilan1 Yu Xin2 Liu Wenjie3 He Jing4 Yang Zhen5

单位：1宁夏医科大学总医院心电图室，银川750004；2宁夏医科大学临床学院检验系，银川750004；3宁夏医科大学中医学院，银川750004；4宁夏医科大学总医院老年与特需医学科，银川750004；5宁夏医科大学总医院心脏中心，银川750004

英文单位：1Electrocardiogram Room General Hospital of Ningxia Medical University Yinchuan 750004 China; 2Department of Laboratory Medicine Clinical College Ningxia Medical University Yinchuan 750004 China; 3College of Traditional Chinese Medicine Ningxia Medical University Yinchuan 750004 China; 4Department of Geriatric and Special Needs Medicine General Hospital of Ningxia Medical University Yinchuan 750004 China; 5Heart Center General  Hospital of Ningxia  Medical University Yinchuan 750004 China

关键词：自发性高血压大鼠；心肌纤维化；沙库巴曲缬沙坦；钙调神经磷酸酶；活化T细胞核因子3

英文关键词：Spontaneouslyhypertensiverats;Myocardialfibrosis;Sacubitril/valsartan;Calcineurin; NuclearfactorofactivatedTcell-3

• 摘要：

• 目的  探讨沙库巴曲缬沙坦对自发性高血压大鼠（SHR）心肌钙调神经磷酸酶/活化T细胞核因子3（CaN/NFAT3）信号通路的影响。方法  选择16只16周龄雄性SHR完全随机分为模型组（8只)和治疗组（8只)，选择相同周龄的8只血压正常的Wistar-Kyoto大鼠作为对照组。治疗组大鼠给予沙库巴曲缬沙坦65 mg/kg，对照组和模型组大鼠给予等容积0.9%氯化钠溶液，均每天1次灌胃，连续4周。干预4周后，超声心动图检测各组大鼠心脏舒张期室间隔厚度(IVSd)和左心室舒张期后壁厚度(LVPWd)；组织病理学评估心肌细胞形态及心肌纤维化程度；免疫组织化学染色和蛋白质印迹法检测心肌组织CaN和NFAT3蛋白表达情况。结果  干预后，模型组大鼠IVSd、LVPWd均高于对照组［（2.53±0.35）mm比（1.28±0.14）mm、（2.32±0.29）mm比（1.31±0.12）mm］，而治疗组大鼠IVSd、LVPWd［（2.02±0.15）mm、（1.85±0.14）mm］均低于模型组（均P＜0.01）。模型组心肌细胞横截面积和心肌胶原纤维百分比均明显高于对照组，而治疗组心肌细胞横截面积和心肌胶原纤维百分比均低于模型组(均P＜0.01)。免疫组织化学染色结果显示，模型组心肌组织CaN蛋白表达水平高于对照组，治疗组CaN蛋白表达水平低于模型组(均P＜0.01)。蛋白质印迹法检测结果显示，模型组CaN蛋白和NFAT3蛋白表达水平均高于对照组［（0.95±0.05）比（0.55±0.05）、（0.84±0.04）比（0.53±0.05）］，而治疗组CaN蛋白和NFAT3蛋白表达水平［（0.65±0.05）、（0.65±0.03）］均低于模型组（均P＜0.01）。结论  沙库巴曲缬沙坦能够减轻SHR心肌纤维化及抑制心肌肥厚，其作用机制可能与抑制CaN/NFAT3信号通路有关。

• Objective  To investigate the effect of sacubitril/valsartan on calcineurin/nuclear factor of activated T cell-3 (CaN/NFAT3) signaling pathway in myocardium of spontaneously hypertensive rats (SHR). Methods  Sixteen male SHR aged 16 weeks old were randomly divided into model group (8 rats) and treatment group (8 rats). Eight normal blood pressure Wistar-Kyoto rats of the same age were selected as control group. The rats in the treatment group were given 65 mg/kg of sacubitril/valsartan, and the rats in the control group and the model group were given the same dose of 0.9% sodium chloride solution. The three groups were treated by gavage once a day for 4 weeks. After 4 weeks of intervention, intraventricular septum diastole thickness (IVSd) and left ventricular diastolic posterior wall thickness (LVPWd) were measured by echocardiography. The morphology of cardiomyocytes and the degree of myocardial fibrosis were evaluated by histopathology. Immunohistochemical staining and western blotting were used to detect the expression of CaN and NFAT3 protein in myocardial tissue. Results  After the intervention, IVSd and LVPWd of rats in the model group were higher than those in the control group［（2.53±0.35）mm vs （1.28±0.14）mm, （2.32±0.29）mm vs （1.31±0.12）mm］, while IVSd and LVPWd of rats in the treatment group［（2.02±0.15）mm, （1.85±0.14）mm］ were lower than those in the model group (all P＜0.01). The cross-sectional area of cardiomyocytes and the percentage of myocardial collagen fibers in the model group were significantly larger than those in the control group, while the cross-sectional area of cardiomyocytes and the percentage of myocardial collagen fibers in the treatment group were significantly lower than those in the model group (all P＜0.01). Immunohistochemical staining showed that the relative expression of CaN protein in the model group was higher than that in the control group, and the relative expression of CaN protein in the treatment group was lower than that in the model group (both P＜0.01). Western blotting analysis showed that the expression levels of CaN protein and NFAT3 protein in the model group were higher than those in the control group ［（0.95±0.05） vs （0.55±0.05）,（0.84±0.04） vs （0.53±0.05）］, while the expression levels of CaN protein and NFAT3 protein in the treatment group ［（0.65±0.05）, （0.65±0.03）］ were lower than those in the model group (all P＜0.01). Conclusions  Sacubitril/valsartan can alleviate myocardial fibrosis, inhibite myocardial hypertrophy in SHR，and its mechanism may be related to the inhibition of CaN/NFAT3 signaling pathway.