title: Up-regulation of arginase II contributes to pulmonary vascular endothelial cell dysfunction during experimental pulmonary embolism.
abstract: Pulmonary embolism (PE) causes pulmonary hypertension by mechanical obstruction and constriction of non-obstructed vasculature. We tested if experimental PE impairs pulmonary vascular endothelium-dependent dilation via activation of arginase II. Experimental PE was induced in male Sprague-Dawley rats by infusing 25 μm microspheres in the right jugular vein, producing moderate pulmonary hypertension. Shams received vehicle injection. Pulmonary arterial rings were isolated after 18 h and isometric tensions were determined. Dilations were induced with acetylcholine, calcium ionophore A23187 or nitroglycerin (NTG) in pre-contracted rings (phenylephrine). Protein expression was assessed by Western blot and immunohistochemistry. Arginase activity was inhibited by intravenous infusion of N(w)-hydroxy-nor-l-arginine (nor-NOHA). l-Arginine supplementation was also given. Endothelium-dependent dilation responses were significantly reduced in PE vs. vehicle-treated animals (ACh: 50 ± 9% vs. 93 ± 3%; A23187: 19 ± 7% vs. 85 ± 7%, p < 0.05), while endothelium-independent dilations (NTG) were unchanged. Endothelial nitric oxide synthase (eNOS) protein content was unchanged by PE. Expression of arginase II increased 4.5-fold and immunohistochemistry revealed increased arginase II staining. Nor-NOHA treatment and l-arginine supplementation significantly improved pulmonary artery ring endothelium-dependent dilation in PE (ACh: 58 ± 6% PE, 88 ± 6% PE + nor-NOHA, 84 ± 4% PE + l-arginine). Experimental PE impairs endothelium-dependent pulmonary artery dilation, while endothelium-independent dilation remains unchanged. The data support the conclusion that up-regulation of arginase II protein expression contributes to pulmonary artery endothelial dysfunction in this model of experimental PE.
authors.affiliation: Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC, USA. jwatts@carolinas.org
authors.forename: John A
authors.initials: JA
authors.lastname: Watts
authors.forename: Michael R
authors.initials: MR
authors.lastname: Marchick
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gellar
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kline
mesh_terms: D000818:Animals; D001119:Arginase / Q000502:physiology*; D001120:Arginine / Q000494:pharmacology; D042783:Endothelial Cells / Q000502:physiology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D011651:Pulmonary Artery / Q000503:physiopathology*; D011655:Pulmonary Embolism / Q000201:enzymology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014664:Vasodilation
chemical_list: D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C113162:Arg2 protein, rat; D001119:Arginase