Xu Weiling, Kaneko F Takao, Zheng Shuo, Comhair Suzy A A, Janocha Allison J, Goggans Tannishia, Thunnissen Frederik B J M, Farver Carol, Hazen Stanley L, Jennings Constance, Dweik Raed A, Arroliga Alejandro C, Erzurum Serpil C
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
FASEB J. 2004 Nov;18(14):1746-8. doi: 10.1096/fj.04-2317fje. Epub 2004 Sep 13.
Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I-III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high-level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.
肺动脉高压（PAH）是一种病因不明的致命疾病，其特征是肺血流动力学调节和血管生长受损，与肺一氧化氮（NO）水平降低有关。基于其在介导血管舒张和细胞生长中的关键作用，NO的减少被认为与PAH的发病机制有关。我们评估了PAH患者和健康对照中NO水平降低和肺动脉高压的机制，包括一氧化氮合酶（NOS）以及调节NOS活性的因素，即底物精氨酸、精氨酸酶的表达和活性，以及NOS的内源性抑制剂。PAH患者的肺组织中NOS I - III表达正常，但底物精氨酸水平与肺动脉压力呈负相关。精氨酸酶是一种通过对精氨酸的作用来调节NO生物合成的酶，其在PAH患者血清中的活性高于对照组，通过免疫染色发现高水平的精氨酸酶表达定位于肺内皮细胞。此外，来自PAH患者肺组织的肺动脉内皮细胞在体外具有更高的精氨酸酶II表达且产生的NO比对照细胞少。因此，底物可用性影响NOS活性和血管舒张，这表明精氨酸酶II和精氨酸代谢途径的改变参与了PAH的病理生理学过程。
