缬沙坦抑制大鼠颈动脉球囊损伤后血管内膜增生的作用机制研究

MECHANISM OF VALSARTAN IN THE INHIBITION OF VASCULAR INTIMAL HYPERPLASIA AFTER CAROTID BALLOON INJURY IN RATS

目的探究缬沙坦(valsartan)抑制大鼠颈动脉球囊损伤后血管内膜增生的作用机制。方法选取40只6周龄SPF级SD大鼠体,体质量(200±30)g,制作大鼠颈动脉球囊损伤模型并分为4组:空白对照组、模型组、低浓度缬沙坦组[10 mg/(g·d)]、高浓度缬沙坦组[20 mg/(g·d)],14 d后取损伤血管段并测定内膜增生情况;使用放射免疫分析血浆内皮素1(ET1)、血栓素B2(TXB2)、6-酮-前列腺素1α(6-keto-PGF1α)含量;使用免疫组织化学法检测血管壁增殖细胞核抗原(PCNA)的表达情况,使用Western blot检测碱性成纤维细胞因子(b-FGF)、转化生长因子(TGF-β1)和血小板源性生长因子(PDGF-BB)的表达情况。结果相比空白对照组,模型组内膜面积、内膜/中膜比值、内膜厚度、ET1、TXB2含量、PCNA阳性指数、b-FGF、TGF-β1和PDGF-BB蛋白表达量显著升高,管腔面积、6-keto-PGF1α含量显著降低,差异有统计学意义(P<0.01);相比模型组,低浓度缬沙坦组和高浓度缬沙坦组,内膜面积、内膜/中膜比值、内膜厚度、ET1、TXB2含量、管腔狭窄度、PCNA阳性指数、b-FGF、TGF-β1和PDGF-BB蛋白表达量显著降低,且高浓度缬沙坦组显著低于低浓度缬沙坦组,差异有统计学意义(P<0.01);相比模型组,低浓度缬沙坦组和高浓度缬沙坦组大鼠管腔面积、6-keto-PGF1α含量显著升高,高浓度缬沙坦组显著高于低浓度缬沙坦组,差异有统计学意义(P<0.01)。结论缬沙坦可以抑制大鼠颈动脉球囊损伤后血管内膜增生,其作用机制与抑制相关生长因子和血管内膜平滑肌的增殖有关,且在一定范围内呈浓度依赖。

Objective To explore the role mechanism of valsartan in the inhibition of vascular intimal hyperplasia after carotid balloon injury in rats.Methods A total of forty 6-week-old SPF SD rats weighing(200±30)g were selected and used to make rat carotid balloon injury models and divided into four groups,including blank control group,model group,low-concentration valsartan group(10 mg/g·d),high-concentration valsartan group(20 mg/g·d).After 14 d,the injured vascular segments were taken and the intimal hyperplasia was measured.Plasma endothelin-1(ET1),thromboxane B2(TXB2)and 6-keto-prostaglandin 1α(6-keto-PGF1α)were analyzed by radioimmunoassay.Immunohistochemistry was used to detect the expression level of proliferating cell nuclear antigen(PCNA)in vascular wall,and Western blot was used to detect the expression levels of basic fibroblast growth factor(b-FGF),transforming growth factor(TGF-β1)and platelet-derived growth factor(PDGF-BB).Results Compared with blank control group,the intimal area,intima/tunica media ratio,intima thickness,ET1 and TXB2 contents,PCNA positive index and protein expression levels of b-FGF,TGF-β1 and PDGF-BB significantly increased in model group,and the lumen area and 6-keto-PGF1αcontent significantly decreased(P<0.01).Compared with model group,the intima area,intima/tunica media ratio,intima thickness,ET1 and TXB2 contents,luminal stenosis,PCNA positive index and protein expression levels of b-FGF,TGF-β1 and PDGF-BB significantly decreased in low-concentration valsartan group and high-concentration valsartan group,and the indexes in high-concentration valsartan group significantly lower than those in low-concentration valsartan group(P<0.01).Compared with model group,the luminal area and 6-keto-PGF1αcontent in low-concentration valsartan group and high-concentration valsartan group increased significantly,and the indexes in high-concentrations valsartan group significantly higher than those in low-concentration valsartan group(P<0.01).Conclusion Valsartan can inhibit the vascular intimal hyperplasia after carotid balloon injury in rats.And its role mechanism is related to the inhibition of proliferation of related growth factors and endothelium smooth muscle,and it is concentration dependent in a certain range.