title: Indoleamine 2,3-diooxygenase in periaortic fat: mechanisms of inhibition of contraction.
abstract: Indoleamine 2,3-dioxygenase (IDO) metabolizes L-tryptophan to L-kynurenine, promotes immunosuppression, and has been described as a consumer of superoxide. We discovered IDO expression in periaortic fat and tested the hypothesis that periarterial IDO functionally reduces agonist-induced contraction. Our model was the thoracic aorta, abdominal aorta, and superior mesenteric artery of the male Sprague-Dawley rat. Periaortic fat from the thoracic aorta stained intensely for IDO, the brown fat marker uncoupling protein-1, and oil red O as a general lipid marker. White fat around the mesenteric artery and abdominal aorta stained less for IDO; brown fat was less abundant. IDO activity (kynurenine-to-tryptophan ratio via HPLC) was detected in visceral and mesenteric artery fat (ratio: ∼4) but was highest in perithoracic aortic fat (ratio: 10 ± 1.1). In isometric contractile experiments, periadventitial fat reduced ANG II-induced thoracic aortic (with fat: 34% of without fat) and mesenteric artery (with fat: 63% of without fat) maximal contraction. In contrast, periadventitial fat did not reduce agonist-induced contraction in the abdominal aorta. The IDO inhibitor 1-L-methyltryptophan (1-MT) reversed the fat-induced reduction of ANG II-induced contraction in the thoracic aorta but not in the mesenteric artery. The IDO metabolite kynurenine relaxed the thoracic aorta only at high (9 mM) concentrations, whereas the downstream metabolite quinolinic acid (1 mM) relaxed the contracted thoracic aorta (∼80%). 1-MT did not correct the reduction in basal superoxide levels observed in the presence of perithoracic aortic fat. We conclude that IDO is an enzyme active primarily in brown fat surrounding the thoracic aorta and depresses aortic contractility.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824-1317, USA. wattss@msu.edu
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
authors.forename: Samantha
authors.initials: S
authors.lastname: Shaw
authors.forename: Robert
authors.initials: R
authors.lastname: Burnett
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dorrance
mesh_terms: D000166:Acridines; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D052436:Adipose Tissue, White / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology / Q000502:physiology; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism*; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000378:metabolism*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D017538:Mesenteric Artery, Superior / Q000201:enzymology / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000166:Acridines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; C033472:10,10'-dimethyl-9,9'-biacridinium; D014364:Tryptophan