肥胖合并动脉粥样硬化大鼠血管内皮依赖性舒张功能以及亲环素A和p-ERK1/2表达的变化

摘要

目的：观察肥胖合并动脉粥样硬化（动脉硬化）大鼠血管内皮功能的改变以及亲环素A（CyPA）和磷酸化细胞外信号调节激酶1/2（p-ERK1/2）的表达变化。　　方法：雄性Wistar大鼠30只随机分为3组，对照组（10只）、动脉硬化组（10只），肥胖+动脉硬化组（10只）。对照组给予基础饲料+腹腔注射等量生理盐水；动脉硬化组基础饲料8周后给予高脂饲料+维生素D3注射液60万IU/kg一次性腹腔注射；肥胖+动脉硬化组给予高脂饲料（肥胖症模型，高脂喂养8周体重大于其余组大鼠20%）+维生素D3注射液60万IU/kg一次性腹腔注射。16周后测定血管内皮依赖性舒张功能；苏木素—伊红（HE）染色、免疫组化检测动脉血管壁CyPA及p-ERK1/2的表达。　　结果：与对照组相比，动脉硬化组、肥胖+动脉硬化组血管内皮依赖性舒张功能下降[（72.49±3.27）% vs （96.63±3.85）%]，[（42.28±2.62）% vs（96.63±3.85）%]，且肥胖+动脉硬化组下降更明显[（42.28±2.62）%vs（72.49±3.27）%]，三组比较差异均有统计学意义（P均<0.05）。HE染色显示，三组大鼠血管壁分别为正常结构，内皮细胞破坏、平滑肌细胞增生和粥样钙化斑块形成等不同程度病变特征。免疫组化提示三组大鼠血管内皮及平滑肌细胞内CyPA及p-ERK1/2表达逐渐升高，组间两两比较差异均有统计学意义（P均<0.05）。　　结论：肥胖+动脉硬化组大鼠血管内皮依赖性舒张功能显著下降，动脉硬化钙化斑块严重，CyPA及p-ERK1/2表达显著增加。推测CyPA、p-ERK1/2信号机制参与肥胖症加重血管动脉硬化进展，肥胖可能是动脉硬化病变的独立危险因素。%Objective: To observe the endothelial-dependent vasodilatation and expressions of cyclophilin A (CyPA), phosphorylated extracellular signal regulated kinase1/2 (p-ERK1/2) in experimental rats with obesity combining atherosclerosis. Methods: A total of 30 male Wistar rats were randomly divided into 3 groups:Control group, the rats received basic diet followed by intraperitoneal injection of normal saline;Atherosclerosis (AS) group, the rats received basic diet for 8 weeks followed by high cholesterol diet with intraperitoneal injection of a single dose vitamin D3 600,000 IU/kg; Obesity+AS group, the rats received high cholesterol diet for 8 weeks (which made their body weights at 20%higher than the other 2 groups) followed by intraperitoneal injection of a single dose vitamin D3 600,000 IU/kg. n=10 in each group. 16 weeks later, the endothelial-dependent vasodilatation was examined in all rats, expressions of CyPA and p-ERK1/2 in arterial wall were detected by HE staining and immunohistochemistry. Results: Compared with Control group, both AS group and Obesity+AS group had reduced endothelial-dependent vasodilatation (72.49 ± 3.27)%and (42.28 ± 2.62)%vs (96.63 ± 3.85)%, such reduction was even more in Obesity+AS group (42.28 ± 2.62)%vs (72.49 ± 3.27)%, all P<0.05. HE staining displayed that in Control group, AS group and Obesity+AS group had normal vessel structure, the endothelial cell damage, vessel smooth muscle cell proliferation, atherosclerosis and calcification plaques at different degrees;immunohistochemistry indicated that the expressions of CyPA and p-ERK1/2 in endothelial and smooth muscle cells were increased accordingly in above 3 groups, all P<0.05 between any 2 groups. Conclusion: The rats with obesity and AS had decreased endothelial-dependent vasodilatation, severe atherosclerosis and calciifcation plaques, increased expressions of CyPA and p-ERK1/2, which speculated that obesity might be an independent risk factor for atherosclerosis.