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Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension
Author(s) -
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.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2317fje
Subject(s) - arginase , medicine , pulmonary hypertension , cardiology , chemistry , biochemistry , arginine , amino acid
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.