title: Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction.
abstract: Endothelial dysfunction contributes to the development of vascular complication in diabetes. Arginase has emerged as a key mechanism behind endothelial dysfunction by its reciprocal regulation of nitric oxide production by substrate competition. We hypothesized that increased arginase activity in patients with type 2 diabetes shifts the metabolism of l-arginine from nitric oxide synthase to arginase resulting in an increase in the plasma ratio of ornithine/citrulline, and that this ratio is associated with endothelial dysfunction.
  
  
  
  Forearm endothelium-dependent vasodilatation and endothelium-independent vasodilatation were determined in 15 patients with type 2 diabetes and 10 healthy controls and related to amino acids reflecting arginase and nitric oxide synthase activity.
  
  
  
  Compared to healthy controls, patients with diabetes had impaired endothelium-dependent vasodilatation and endothelium-independent vasodilatation. The ratios of ornithine/citrulline and proline/citrulline were 60% and 95% higher, respectively, in patients with diabetes than in controls (p < 0.001). The plasma ornithine/arginine ratio was 36% higher in patients with diabetes, indicating increased arginase activity. These ratios were inversely correlated to endothelium-dependent vasodilatation and endothelium-independent vasodilatation.
  
  
  
  Patients with diabetes and macrovascular complications have increased amino acid ratios reflecting a shift in arginine metabolism due to arginase activation. These changes are inversely related to endothelial function supporting that arginase activity contributes to endothelial dysfunction.
authors.affiliation: Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Department of Cardiology Karolinska University Hospital, Stockholm, Sweden oskar.kovamees@ki.se.
authors.forename: Oskar
authors.initials: O
authors.lastname: Kövamees
authors.affiliation: Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Department of Cardiology Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Alexey
authors.initials: A
authors.lastname: Shemyakin
authors.affiliation: Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Department of Cardiology Karolinska University Hospital, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Pernow
mesh_terms: D000368:Aged; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002956:Citrulline / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications*; D003925:Diabetic Angiopathies / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000503:physiopathology; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009952:Ornithine / Q000097:blood; D015854:Up-Regulation; D014664:Vasodilation
chemical_list: D015415:Biomarkers; D002956:Citrulline; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D001119:Arginase
keywords: Arginase; coronary artery disease; endothelial function; nitric oxide