L-Arginine restores endothelial nitric oxide synthase-coupled activity and attenuates monocrotaline-induced pulmonary artery hypertension in rats

Ou ZJ, Wei W, Huang DD, Luo W, Luo D, Wang ZP, Zhang X, Ou JS. L-Arginine restores endothelial nitric oxide synthase-coupled activity and attenuates monocrotaline-induced pulmonary artery hypertension in rats. Am J Physiol Endocrinol Metab 298: E1131-E1139, 2010. First published March 9, 2010; doi:10.1152/ajpendo.00107.2010.-L-Arginine can attenuate pulmonary hypertension (PH) by a mechanism that are not fully understood. This study investigated the molecule mechanism of L-arginine attenuating PH. Sprague Dawley rats were treated with monocrotaline (MCT) with or without L-arginine for 3 or 5 wk. Right ventricular systolic pressure (RVSP), right heart hypertrophy, survival rate, pulmonary artery wall thickness, nitric oxide (NO) concentration, and superoxide anion (O-2(center dot-)) generation in the lung were measured. Expressions of endothelial nitric oxide synthase (eNOS) and heat shock protein 90 (HSP90), phosphorylation of eNOS at Ser(1177), and the association of eNOS and HSP90 in the lung were determined by Western blot and immunoprecipitation experiments. MCT increased RVSP, right heart hypertrophy, mortality, pulmonary artery wall thickness, and O-2(center dot-) generation and decreased eNOS and HSP90 expression and association, phosphorylation of eNOS at Ser1177, and NO production. L-Arginine decreased RVSP, right heart hypertrophy, mortality, O-2(center dot-) generation, and pulmonary artery wall thickness and increased NO production. L-Arginine increased eNOS expression, phosphorylation of eNOS at Ser1177, and association of eNOS and HSP90 without significantly altering HSP90 expression. L-Arginine may act through three pathways, providing a substrate for NO generation, preserving eNOS expression/phosphorylation, and maintaining the association of eNOS and HSP90, which allows restoration of eNOS activity and coupling activity, to maintain the balance between NO and O-2(center dot-) and delay the development of PH.