Wang Xian-min, Zhou Tong-fu, Liu Bin, Wei Li, Shi Kun, Zhao Shan-shan, Hua Yi-min, Liu Han-ming
Department of Padiatric Cardiology, West China Second Hospital, Sichuan University, Chengdu 610041, China.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2009 Mar;40(2):255-9.
To determine the effect of captopril and losartan on the expressions of matrix metalloproteinase-2,9 (MMP-2,9) and metalloproteinase-1 (TIMP-1) in rats with pulmonary arterial hypertension, and the mechanisms of captopril and losartan in intervening the development of pulmonary arterial hypertension.
Forty male Spraque-Dawley rats were divided into 4 groups randomly: pulmonary arterial hypertension (created by pneumonectomy plus MCT injection) model group (PAH Model), PAH model treated with captopril [PAH+Cap 10 mg/(kg x d)], losartan group [PAH+Los 15 mg/(kg x d)] and normal control group(Control). The mPAP, weight ratio of RV to LV+S, neointima formation, relative thickness of small pulmonary arteries, and degree of muscularization of non-muscular arterioles were measured at day 35. The expression of SM-a-actin in the PASMC was determined by immunochemistry stain. The expressions of MMP-2, 9, TIMP-1 and MMP-2, 9, TIMP-1 mRNA in the pulmonary tissues were determined by immunohistochemistry and FQ-PCR respectively. The enzymatic activity of MMP-2, 9 was measured by Gelatin zymography.
Pneumonectomy plus MCT injection induced severe pulmonary arterial hypertension characterized by neointimal formation. Captopril or losartan suppressed the increase of mPAP, right ventricle weight, thickness of small pulmonary arteries and muscularization of peripheral pulmonary arterioles in the rats with PAH (P < 0.05). The PAH model group had higher expressions of MMP-2, 9, TIMP-1 mRNA and enzymatic activity of MMP-2, 9 in lung tissue than the other groups (P < 0.05). Captopril intervention had similar effects as losartan intervention.
The captopril and losartan induced attenuation of PAH and pulmonary vascular remodeling is likely to be associated with the regulation of the expressions of MMP-2, 9, TIMP-1.
探讨卡托普利和氯沙坦对肺动脉高压大鼠基质金属蛋白酶-2、9（MMP-2、9）及金属蛋白酶组织抑制因子-1（TIMP-1）表达的影响，以及卡托普利和氯沙坦干预肺动脉高压发展的机制。
将40只雄性Spraque-Dawley大鼠随机分为4组：肺动脉高压（肺切除加注射野百合碱造模）模型组（PAH模型组）、卡托普利治疗的PAH模型组[PAH+Cap 10mg/（kg·d）]、氯沙坦组[PAH+Los 15mg/（kg·d）]和正常对照组（对照组）。于第35天测量平均肺动脉压（mPAP）、右心室与左心室加室间隔重量比（RV/LV+S）、新生内膜形成、小肺动脉相对厚度及无肌型小动脉肌化程度。采用免疫组化染色法检测肺动脉平滑肌细胞（PASMC）中平滑肌α-肌动蛋白（SM-α-actin）的表达。分别采用免疫组化法和荧光定量聚合酶链反应（FQ-PCR）检测肺组织中MMP-2、9、TIMP-1的表达及MMP-2、9、TIMP-1 mRNA水平。采用明胶酶谱法检测MMP-2、9的酶活性。
肺切除加注射野百合碱诱导大鼠出现以新生内膜形成为特征的重度肺动脉高压。卡托普利或氯沙坦可抑制PAH大鼠mPAP、右心室重量、小肺动脉厚度及外周肺动脉肌化程度的增加（P<0.05）。PAH模型组肺组织中MMP-2、9、TIMP-1 mRNA表达及MMP-2、9酶活性高于其他各组（P<0.05）。卡托普利干预与氯沙坦干预效果相似。
卡托普利和氯沙坦减轻PAH及肺血管重塑可能与调节MMP-2、9、TIMP-1的表达有关。
