L-arginine restores endothelial nitric oxide synthase-coupled activity and attenuates monocrotaline-induced pulmonary artery hypertension in rats.
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)(*-)) 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)(*-) generation and decreased eNOS and HSP90 expression and association, phosphorylation of eNOS at Ser(1177), and NO production. L-arginine decreased RVSP, right heart hypertrophy, mortality, O(2)(*-) generation, and pulmonary artery wall thickness and increased NO production. L-arginine increased eNOS expression, phosphorylation of eNOS at Ser(1177), 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)(*-) and delay the development of PH.
Ou
Zhi-Jun
ZJ
Division of Hypertension and Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. oujs@mail.sysu.edu.cn
Wei
Wei
W
Huang
Da-De
DD
Luo
Wei
W
Luo
Dan
D
Wang
Zhi-Ping
ZP
Zhang
Xi
X
Ou
Jing-Song
JS
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001794:Blood Pressure; D015153:Blotting, Western; D001835:Body Weight; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018841:HSP90 Heat-Shock Proteins; D009569:Nitric Oxide; D016686:Monocrotaline; D001120:Arginine; D052250:Nitric Oxide Synthase Type III