Division of Hypertension and Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1131-9. doi: 10.1152/ajpendo.00107.2010. Epub 2010 Mar 9.
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.
精氨酸可通过尚未完全阐明的机制减轻肺动脉高压(PH)。本研究探讨了精氨酸减轻 PH 的分子机制。用野百合碱(MCT)处理 Sprague Dawley 大鼠,并用或不用精氨酸处理 3 或 5 周。测量右心室收缩压(RVSP)、右心肥厚、存活率、肺动脉壁厚度、肺中的一氧化氮(NO)浓度和超氧阴离子(O(2)(-))生成。通过 Western blot 和免疫沉淀实验测定肺内皮型一氧化氮合酶(eNOS)和热休克蛋白 90(HSP90)的表达、eNOS 在 Ser(1177)的磷酸化以及 eNOS 和 HSP90 的关联。MCT 增加了 RVSP、右心肥厚、死亡率、肺动脉壁厚度和 O(2)(-)生成,降低了 eNOS 和 HSP90 的表达和关联、eNOS 在 Ser(1177)的磷酸化以及 NO 的生成。精氨酸降低了 RVSP、右心肥厚、死亡率、O(2)(-)生成和肺动脉壁厚度,并增加了 NO 的生成。精氨酸增加了 eNOS 的表达、eNOS 在 Ser(1177)的磷酸化以及 eNOS 和 HSP90 的关联,而没有明显改变 HSP90 的表达。精氨酸可能通过三种途径发挥作用,提供生成 NO 的底物,保持 eNOS 的表达/磷酸化,维持 eNOS 和 HSP90 的关联,从而恢复 eNOS 活性和偶联活性,维持 NO 和 O(2)(-)之间的平衡,延缓 PH 的发展。