title: Arginase 1 contributes to diminished coronary arteriolar dilation in patients with diabetes.
abstract: Arginase 1, via competing with nitric oxide (NO) synthase for the substrate L-arginine, may interfere with NO-mediated vascular responses. We tested the hypothesis that arginase 1 contributes to coronary vasomotor dysfunction in patients with diabetes mellitus (DM). Coronary arterioles were dissected from the right atrial appendages of 41 consecutive patients with or without DM (the 2 groups suffered from similar comorbidities), and agonist-induced changes in diameter were measured with videomicroscopy. We found that the endothelium-dependent agonist ACh elicited a diminished vasodilation and caused constriction to the highest ACh concentration (0.1 μM) with a similar magnitude in patients with (18 ± 8%) and without (17 ± 9%) DM. Responses to ACh were not significantly affected by the inhibition of NO synthesis with N(G)-nitro-L-arginine methyl ester in either group. The NO donor sodium nitroprusside-dependent dilations were not different in patients with or without DM. Interestingly, we found that the presence of N(G)-hydroxy-L-arginine (10 μM), a selective inhibitor of arginase or application of L-arginine (3 mM), restored ACh-induced coronary dilations only in patients with DM (to 47 ± 6% and to 40 ± 19%, respectively) but not in subjects without DM. Correspondingly, the protein expression of arginase 1 was increased in coronary arterioles of patients with DM compared with subjects without diabetes. Moreover, using immunocytochemistry, we detected an abundant immunostaining of arginase 1 in coronary endothelial cells of patients with DM, which was colocalized with NO synthase. Collectively, we provided evidence for a distinct upregulation of arginase 1 in coronary arterioles of patients with DM, which contributes to a reduced NO production and consequently diminished vasodilation.
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Timea
authors.initials: T
authors.lastname: Beleznai
authors.forename: Attila
authors.initials: A
authors.lastname: Feher
authors.forename: David
authors.initials: D
authors.lastname: Spielvogel
authors.forename: Steven L
authors.initials: SL
authors.lastname: Lansman
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology / Q000201:enzymology*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D015854:Up-Regulation; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D001119:Arginase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester