缬沙坦对门静脉高压性胃病大鼠胃黏膜组织TGF-β1/Smad信号传导通路的影响

Valsartan improves portal hypertensive gastropathy in rats possibly via TGF-β1/Smad signaling pathway

目的:探讨缬沙坦对门静脉高压性胃病大鼠胃黏膜病变的疗效和作用机制.方法:48只♂SD大鼠随机分为假手术组、门静脉高压性胃病模型组、缬沙坦预防组、缬沙坦常规剂量组和缬沙坦加倍剂量组.采用部分门静脉主干缩窄法制备门静脉高压性胃病模型.免疫组织化学染色法检测各组大鼠胃黏膜组织转化生长因子-β1(transforming growth factor-β1,TGF-β1)表达、微血管密度(microvessel density,MVD),Western blot分析胃黏膜组织Smad2、Smad7蛋白表达.ELISA法检测各组血清肾素(plasma renin activity,PRA)、血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)、谷氨酸转氨酶(alanine aminotransferase,ALT)、白蛋白(albumin,ALB)水平.结果:缬沙坦预防组、常规剂量组和加倍剂量组胃黏膜组织中TGF-β1(11.58±2.27,13.29±2.82,13.15±3.36)明显低于造模组(24.25±3.48)(P<0.05);缬沙坦预防组、常规剂量组和加倍剂量组胃黏膜微血管密度值(12.08±2.34;13.13±1.42;12.04±1.02)亦明显低于造模组(17.09±5.52)(P<0.05);缬沙坦预防组、常规剂量组和加倍剂量组胃黏膜组织中Smad2蛋白表达(0.86±0.59,0.82±0.36,0.83±0.49)较造模组(1.60±0.77)明显下降(P<0.05),但高于假手术组;Smad7蛋白表达(1.59±0.72,1.65±0.80,1.69±0.85)较模型组(0.58±0.35)明显升高(P<0.05),但低于假手术组.缬沙坦预防组、常规剂量组和加倍剂量组血PRA(16.49 ng/mL±2.77 ng/mL;15.92ng/mL±4.30 ng/mL;16.72 ng/mL±5.48 ng/mL)、AngⅡ(1664.44 pg/mL±285.47 pg/mL,1686.82 pg/mL±499.16 pg/mL,1734.07 pg/mL±326.66 pg/mL)水平较模型组(11.49 ng/mL±2.12 ng/mL,1110.38 pg/mL±193.85 pg/mL)比较明显升高(P<0.05,P<0.01).结论:缬沙坦能够改善门静脉高压性胃病大鼠胃黏膜微血管病变,可能是通过下调TGF-β1、Smad2表达,上调Smad7表达发挥作用.

AIM： To investigate the efficacy and mechanisms of action of valsartan on portal hypertensive gastropathy in rats with gastric mucosa lesions. METHODS： Forty-eight SD rats were randomly divided into a sham-operated group, a portal hypertension gastropathy group, a valsartan prevention group, a normal dose valsartan group and a high dose valsartan group. Portal hypertensive gastropathy was induced by the partial portal vein ligation method. Gastric mucosa TGF-beta1 expression and microvessel density （MVD） were detected by immunohistochemical staining method. Gastric mucosa Smad2 and Smad7 protein expression was detected by Western blot. Plasma levels of rennin activity （PRA）, angiotensin II （Ang II）, alanine aminotransferase （ALT）, and albumin （ALB） were determined by ELISA. RESULTS： Compared with the model group, gastric mucosa TGF-β1 （11.58 ± 2.27, 13.29 ± 2.82, 13.15 ± 3.36 vs 24.25 ± 3.48, all P 〈0.05） and Smad2 （0.86 ± 0.59, 0.82±0.36, 0.83 ± 0.49 vs 1.60 ± 0.77, P 〈 0.05） protein expression was significantly decreased in the valsartan prevention group, normal dose valsartan group and high dose valsartan group. Smad7 protein expression in the valsartan prevention group, normal dose valsartan group and high dose valsartan group was significantly higher than that in the model group （1.59 ± 0.72, 1.65 ± 0.80, 1.69 ± 0.85 vs 0.58 ± 0.35, all P 〈 0.05）. Plasma PRA （16.49 ng/mL ± 2.77 ng/mL, 15.92 ng/mL ± 4.30 ng/mL, 16.72 ng/mL ± 5.48 ng/mL vs 11.49 ng/mL ± 2.12 ng/mL, all P 〈0.05） and Ang II （1664.44 pg/mL ± 285.47 pg/mL, 1686.82 pg/mL ± 499.16 pg/mL, 1734.07 pg/mL ± 326.66 pg/mL vs 1110.38 pg/mL ± 193.85 pg/mL, all P 〈0.01） were also significantly higher in the valsartan prevention group, normal dose valsartan group and high dose valsartan group than in the model group. CONCLUSION： Valsartan can improve portal hypertensive gastropathy probably by down-regulating TGF-β1 and Smad2 expression and up-regulating Smad7 expression.