Wang X M, Shi K, Li J J, Chen T T, Guo Y H, Liu Y L, Yang Y F, Yang S
Department of Pediatric Cardiology, Chengdu Women's and Children's Central Hospital, Chengdu, China
Department of Pediatric Cardiology, Chengdu Women's and Children's Central Hospital, Chengdu, China.
Genet Mol Res. 2015 Mar 6;14(1):1707-17. doi: 10.4238/2015.March.6.17.
This study investigated the effects of angiotensin II (AngII) intervention, using captopril and losartan, on the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in rats with pulmonary hypertension, in an effort to understand mechanisms underlying pulmonary vascular remodeling. A total of 40 male Sprague-Dawley rats were randomly divided into normal group, model group, captopril group, and losartan group. After 5 weeks, the mean pulmonary arterial pressure (mPAP), right ventricular index, and neointima formation in each group were determined. Immunohistochemical analysis was performed to determine the degree of pulmonary arterial muscularization as well as MMP-2, MMP-9, and TIMP-1 protein expression in lung tissue. Real-time fluorescent quantitative PCR was used to detect MMP2, MMP9, TIMP1, COL1A1, and COL4A1 mRNA expression. Picro-sirius red staining was performed to detect collagen protein expression. Neointima formation was observed in the model group. Moreover, the mPAP, right ventricular index, degree of arterial muscularization, and collagen deposition, as well as mRNA and protein expression of MMP2, MMP9, and TIMP1 were significantly higher than those in the other groups (P < 0.05). The mPAP, right ventricular index, degree of arterial muscularization, and mRNA and protein expression in the captopril and losartan groups were significantly decreased compared with those of the model group (P < 0.05). AngII regulates MMP-2, MMP-9, and TIMP-1 expression and affects collagen deposition. Thus, this hormone is involved in pulmonary vascular remodeling, indicating a possible mechanism that can be targeted in pulmonary hypertension intervention.
本研究使用卡托普利和氯沙坦，探讨血管紧张素II（AngII）干预对肺动脉高压大鼠基质金属蛋白酶-2（MMP-2）、MMP-9、金属蛋白酶组织抑制剂-1（TIMP-1）及胶原蛋白表达的影响，以了解肺血管重塑的潜在机制。将40只雄性Sprague-Dawley大鼠随机分为正常组、模型组、卡托普利组和氯沙坦组。5周后，测定各组的平均肺动脉压（mPAP）、右心室指数和新生内膜形成情况。采用免疫组织化学分析确定肺动脉肌化程度以及肺组织中MMP-2、MMP-9和TIMP-1蛋白表达。使用实时荧光定量PCR检测MMP2、MMP9、TIMP1、COL1A1和COL4A1 mRNA表达。采用苦味酸-天狼星红染色检测胶原蛋白蛋白表达。模型组观察到新生内膜形成。此外，模型组的mPAP、右心室指数、动脉肌化程度、胶原蛋白沉积以及MMP2、MMP9和TIMP1的mRNA和蛋白表达均显著高于其他组（P<0.05）。与模型组相比，卡托普利组和氯沙坦组的mPAP、右心室指数、动脉肌化程度以及mRNA和蛋白表达均显著降低（P<0.05）。AngII调节MMP-2、MMP-9和TIMP-1的表达并影响胶原蛋白沉积。因此，这种激素参与肺血管重塑，提示在肺动脉高压干预中可能存在可靶向的机制。
