Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension.
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.
Xu
Weiling
W
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Kaneko
F Takao
FT
Zheng
Shuo
S
Comhair
Suzy A A
SA
Janocha
Allison J
AJ
Goggans
Tannishia
T
Thunnissen
Frederik B J M
FB
Farver
Carol
C
Hazen
Stanley L
SL
Jennings
Constance
C
Dweik
Raed A
RA
Arroliga
Alejandro C
AC
Erzurum
Serpil C
SC
D001119:Arginase / Q000378:metabolism*; D001794:Blood Pressure; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D011651:Pulmonary Artery / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism
D009569:Nitric Oxide; C477631:ARG2 protein, human; D001119:Arginase