Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension

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. (C) 2010 Elsevier Inc. All rights reserved.