依那普利和厄贝沙坦对肾血管性高血压大鼠颈动脉重构及转化生长因子β_1/Smads表达的影响

Effects of enalapril and irbesartan on carotid artery remodeling and on transforming growth factorβ_1 / Smads expression in renovascular hypertensive rats

目的观察依那普利和厄贝沙坦单用及联用对肾血管性高血压大鼠(RHR)颈动脉重构及转化生长因子β1(TGF-β1)/Smads表达的影响。方法 8～12周龄雄性Sprague-Dawley(SD)大鼠30只。建立"两肾一夹"RHR模型,设立模型组、假手术组、依那普利组[10mg/(kg·d)]、厄贝沙坦组[50mg/(kg·d)]、联合用药组[厄贝沙坦25mg/(kg·d)+依那普利5mg/(kg·d)],每组6只大鼠。药物连续干预6周。采用HE染色、Masson染色法及免疫组化染色检测颈动脉中膜形态及结构变化并测量中膜厚度、中膜厚度/腔径以及颈动脉中膜α肌动蛋白(α-actin)、增殖细胞核抗原(PCNA)、TGF-β1、磷酸化Smad2/3(p-Smad2/3)、Smad7的表达水平。结果 RHR模型组颈动脉中膜明显肥厚,平滑肌细胞体积增大,排列紊乱;中膜厚度、中膜厚度/腔径、颈动脉中膜平滑肌细胞的增殖指数及胶原纤维面积百分比均高于假手术组[中膜厚度(91.28±11.17)比(52.15±7.18)μm,中膜厚度/腔径(20.75±3.07)%比(9.94±1.52)%,增殖指数(35.31±12.97)%比(1.84±0.52)%,胶原纤维面积百分比(67.53±7.68)%比(15.35±4.47)%,均P<0.01];TGF-β1和p-Smad2/3的表达较假手术组均增多(均P<0.05),Smad7表达较假手术组减少(P<0.01)。依那普利和厄贝沙坦均能改善颈动脉平滑肌肥大和胶原沉积,减小RHR颈动脉中膜厚度、中膜厚度/腔径、平滑肌细胞的增殖指数、胶原纤维面积百分比及TGF-β1和p-Smad2/3的表达(P<0.05),增加Smad7表达(P<0.01),且两药联用较单用更能改善颈动脉重构,降低TGF-β1和p-Smad2/3的表达(P<0.05),增加Smad7表达(P<0.05)。结论依那普利和厄贝沙坦通过影响TGF-β1/Smads信号通路中TGF-β1、p-Smad2/3和Smad7的表达而改善RHR颈动脉重构,且两药联用有协同作用。

Objective To investigate the effects of enalapril and irbesartan administered alone or in combination on carotid artery remodeling and on TGF-β1/Smads expression in renovascular hypertensive rats （RHR）. Methods Thirty Sprague-Dawley （SD） rats aged 8-12 weeks were divided into five groups： model group （n= 6）, shamZoper ated group （n=6）, enalapril group [enalapril 10 mg/（kg · d）, n=6], irbesartan group [irbesartan 50 mg/（kg · d）, n=6] and combination group [enalapril 5 mg/（kg · d） and irbesartan 25 mg/（kg· d）, n=6]. The RHR model was established by ＂two-kidney and one-clip＂ method and the course lasted for 6 weeks. Morphological and struc tural changes in the media of carotid artery were observed by hematoxylin and eosin （HE） staining, Masson staining and immunochemical staining. Media thickness （MT） , MT and lumen diameter ratio （MT/LD） , and the expres sion levels of media a-smooth muscle actin （a-actin）, proliferating cell nuclear antigen （PCNA） , TGF-β1 , phospho- rylated Smad 2/3 （p-Smad2/3） and Smad7 in carotid arteries were detected. Results The media of carotid arteries in RHR model group was significantly thickened,vascular smooth muscle cells （VSMC） were disarranged and their volume was increased. MT, MT/LD, the the proliferation index of VSMC and the percentage of collagen fiber area in model group were significantly higher than those in sham-operated group [-MT （91.28 ±11.17） vs （52.15 ± 7.18）μm, MT/LD （20.75±3.07] % vs （9.94±1.52）%, proliferation index （35.31±12.97）% vs （1. 84±0.52）%,percentage of collagen area （67.53±7.68）% vs （15.35±4.47）%, all P〈0.01]. Compared to sham-operated group, model group rats demonstrated significantly higher expressions of TGF -β1 and p smad2/3 while lower expres sion of Smad7 （ both P〈0. 05 ）. Enalapril and irbesartan administered alone improved VSMC hypertrophy and colla gen deposition, reduced RHR carotid MT, MT/LD, VSMC proliferation index the percentage of collagenous fibre area and expression of TGF-β1 and p-Smad2/3 （ P 〈 0.05 ）, upregulated Smad7 expression （ P 〈 0.01 ）. Moreover, those effects of enalapril and irbesartan combined were more significant （all P〈 0.05 ）. Conclusion Enalapril or Irbesartan can improve carotid remodeling through affecting the expressions of TGF β1 , p-Smad2/3, and Smad7 in RHR. And the combination of enalapril and irbesartan display synergetic effects.