title: Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus.
abstract: BACKGROUND
  Endothelial dysfunction plays an important role in the early development of atherosclerosis and vascular complications in type 2 diabetes mellitus. Increased expression and activity of arginase, metabolizing the nitric oxide substrate l-arginine, may result in reduced production of nitric oxide and thereby endothelial dysfunction. We hypothesized that inhibition of arginase activity improves endothelial function in patients with coronary artery disease (CAD) and type 2 diabetes mellitus.
  
  
  RESULTS
  Three groups of subjects were included: 16 patients with CAD, 16 patients with CAD and type 2 diabetes mellitus (CAD+Diabetes), and 16 age-matched healthy control subjects. Forearm endothelium-dependent and endothelium-independent vasodilatation were assessed with venous occlusion plethysmography before and during intra-arterial infusion of the arginase inhibitor N(ω)-hydroxy-nor-l-arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also coinfused with the nitric oxide synthase inhibitor (N(G)-monomethyl L-arginine). The expression of arginase was determined in the internal mammary artery of patients undergoing bypass surgery. Nor-NOHA markedly increased endothelium-dependent vasodilatation (up to 2-fold) in patients with CAD+Diabetes and CAD (P<0.001) but not in the control group. N(G)-monomethyl L-arginine completely inhibited the increase in endothelium-dependent vasodilatation induced by nor-NOHA. Endothelium-independent vasodilatation was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes mellitus.
  
  
  CONCLUSIONS
  Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes mellitus suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction.
authors.affiliation: Karolinska University Hospital Solna, CMM, L8:03, S-17176, Stockholm, Sweden.   alexey.shemyakin@ki.se.
authors.forename: Alexey
authors.initials: A
authors.lastname: Shemyakin
authors.forename: Oskar
authors.initials: O
authors.lastname: Kövamees
authors.forename: Arnar
authors.initials: A
authors.lastname: Rafnsson
authors.forename: Felix
authors.initials: F
authors.lastname: Böhm
authors.forename: Peter
authors.initials: P
authors.lastname: Svenarud
authors.forename: Magnus
authors.initials: M
authors.lastname: Settergren
authors.forename: Christian
authors.initials: C
authors.lastname: Jung
authors.forename: John
authors.initials: J
authors.lastname: Pernow
mesh_terms: D000368:Aged; D001119:Arginase / Q000032:analysis / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D014664:Vasodilation
chemical_list: C404735:N(omega)-hydroxynorarginine; D009569:Nitric Oxide; D001120:Arginine; D001119:Arginase