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目的:观察Rho激酶(ROCKⅠ)及转化生长因子β1(TGF-β1)在慢性血栓栓塞性肺动脉高压大鼠肺小动脉表达的动态变化。方法:雄性Wistar大鼠64只,随机分为8组,每组8只:初始对照组、栓塞3 d组、1周组、2周组、4周组、8周组、12周组、终末对照组。采血制备血栓,颈静脉注入,2周后第2次栓塞,全程腹腔注射氨甲环酸。达实验设定日期后,测各组大鼠平均肺动脉压(mPAP)、肺动脉相对中膜厚度(PAMT)、管壁面积/管总面积(WA/TA)、右室肥厚指数(RVHI),原位杂交检测ROCKⅠmRNA表达,免疫组化检测TGF-β1蛋白表达。结果:栓塞4周组至12周组大鼠随时间延长mPAP明显增高(均P<0.01);PAMT、WA/TA在4周后随时间延长显著增高(4周组P<0.05,8周、12周组P<0.01);8周后RVHI较对照组明显增高(8周组P<0.05,12周组P<0.01);栓塞后ROCKⅠmRNA原位杂交染色强度随时间延长出现增高趋势(3 d组至2周组P<0.05,4周组至12周组P<0.01),TGF-β1蛋白免疫组化染色强度随时间延长出现增高趋势(1周组、2周组P<0.05,4周组至12周组P<0.01)。相关分析表明,ROCKⅠmRNA及TGF-β1蛋白与mPAP、RVHI及血管重构指标均呈正相关(均P<0.01);ROCKⅠmRNA与TGF-β1蛋白表达呈正相关(r=0.612,P<0.01)。结论:ROCKⅠ和TGF-β1均可能参与慢性血栓栓塞性肺动脉高压、肺血管重构的病理生理过程,此过程中Rho/Rho激酶信号通路可能是TGF-β1发挥生物学效应的重要途径之一。
OBJECTIVE: To observe the dynamic changes of Rho-kinase (ROCK) and transforming growth factor-β1 (TGF-β1) expression in pulmonary arterioles of rats with chronic thromboembolic pulmonary hypertension. Methods: Sixty-four male Wistar rats were randomly divided into 8 groups with 8 rats in each group: initial control group, 3-day embolization group, 1 week group, 2 weeks group, 4 weeks group, 8 weeks group, 12 weeks group, The last control group. Blood preparation thrombus, jugular vein injection, 2 weeks after the second embolization, the entire intraperitoneal injection of tranexamic acid. After reaching the experimental setting date, the mean pulmonary arterial pressure (mPAP), pulmonary arterial relative media thickness (PAMT), total wall area / total area (WA / TA), RVHI, ROCK I mRNA expression was detected by hybridization and the expression of TGF-β1 protein was detected by immunohistochemistry. Results: After 4 weeks and 12 weeks of embolization, the mPAP of rats in the four groups increased significantly with time (P <0.01, P <0.01) (P <0.01, P <0.01, P <0.01). After 8 weeks, the RVHI was significantly higher than that of the control group (P <0.05 for 8 weeks, P <0.01 for 12 weeks); the staining intensity of ROCK I mRNA in situ hybridization increased with time (P <0.05). The intensity of immunohistochemical staining of TGF-β1 increased with time prolonged (1 week group, 2 weeks group P <0.05, 4 weeks Group to 12 weeks group P <0.01). Correlation analysis showed that ROCKⅠmRNA and TGF-β1 protein were positively correlated with mPAP, RVHI and vascular remodeling (all P <0.01). ROCKⅠmRNA and TGF-β1 protein expression were positively correlated (r = 0.612, P <0.01). CONCLUSION: Both ROCKⅠ and TGF-β1 may be involved in the pathophysiological process of chronic thromboembolic pulmonary hypertension and pulmonary vascular remodeling. Rho / Rho kinase signaling pathway may be one of the important pathways of TGF-β1 biological effects in this process.