Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China.
Vascul Pharmacol. 2010 Nov-Dec;53(5-6):223-9. doi: 10.1016/j.vph.2010.09.002. Epub 2010 Sep 16.
Recent studies have shown that the plasma level of asymmetric dimethylarginine (ADMA) was increased accompanied by the decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in pulmonary hypertension (PH) and ADMA was able to regulate pulmonary endothelial cells mobility through increasing the activity of Rho kinase (ROCK). This work was conducted to explore the role of ADMA/DDAH pathway in vascular remodeling in PH and the underlying mechanisms. The rat model of PH was established by a single injection of monocrotaline (60 mg/kg, s.c.). The pulmonary arterial pressure, the remodeling of pulmonary artery, the hypertrophy of right ventricle, the plasma levels of ADMA and NO, the expression of DDAH2, ROCK1 or ROCK2 and the ROCK activity were determined. In vitro studies, the pulmonary artery smooth muscle cells (PASMCs) were isolated and cultured. The effect of ADMA on PASMCs proliferation and ROCK activation was investigated. The results showed that the injection of monocrotaline successfully induced PH characterized by the increased pulmonary arterial pressure, vascular remodeling and right ventricle hypertrophy. The plasma level of ADMA was elevated concomitantly with the increased ROCK activity and ROCK1 expression as well as the decreased DDAH2 expression in pulmonary arteries. In the cultured PASMCs, ADMA promoted cellular proliferation accompanied by the increased ROCK1 expression and ROCK activity, which was attenuated by the ROCK inhibitor or by the intracellular antioxidant. These results suggest that ADMA could promote the proliferation of PASMCs through activating ROCK pathway, which may account for, at least partially, the vascular remodeling in monocrotaline-induced PH.
最近的研究表明，肺动脉高压（PH）患者的血浆不对称二甲基精氨酸（ADMA）水平升高，同时二甲基精氨酸二甲胺水解酶（DDAH）活性降低，ADMA 能够通过增加 Rho 激酶（ROCK）的活性来调节肺内皮细胞的迁移。本研究旨在探讨 ADMA/DDAH 通路在 PH 血管重构中的作用及其机制。通过单次皮下注射野百合碱（60mg/kg）建立 PH 大鼠模型。测定肺动脉压、肺动脉重构、右心室肥厚、血浆 ADMA 和 NO 水平、DDAH2、ROCK1 或 ROCK2 的表达及 ROCK 活性。在体外研究中，分离和培养肺动脉平滑肌细胞（PASMCs）。研究 ADMA 对 PASMCs 增殖和 ROCK 激活的影响。结果表明，野百合碱注射成功诱导 PH，表现为肺动脉压升高、血管重构和右心室肥厚。血浆 ADMA 水平升高，同时 ROCK 活性和 ROCK1 表达增加，肺动脉中 DDAH2 表达降低。在培养的 PASMCs 中，ADMA 促进细胞增殖，同时 ROCK1 表达和 ROCK 活性增加，用 ROCK 抑制剂或细胞内抗氧化剂可减弱这种作用。这些结果表明，ADMA 可通过激活 ROCK 通路促进 PASMCs 增殖，这可能是野百合碱诱导的 PH 血管重构的部分原因。
