title: Akita spontaneously type 1 diabetic mice exhibit elevated vascular arginase and impaired vascular endothelial and nitrergic function.
abstract: BACKGROUND
  Elevated arginase (Arg) activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO) synthase (NOS) and NO production. Akita mice, a genetic non-obese type 1 diabetes model, recapitulate human diabetes. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC) from Akita mice.
  
  
  RESULTS
  Endothelium-dependent relaxation, Arg and NOS activity, and protein expression levels of Arg and constitutive NOS were assessed in aortas and CC from Akita and non-diabetic wild type (WT) mice at 4, 12 and 24 wks of age. Systolic blood pressure (SBP) was assessed by tail cuff. In aorta and CC, Akita mice exhibited a progressive impairment of vascular endothelial and nitrergic function increased Arg activity and expression (Arg1 in aorta and both Arg1 and Arg2 in CC) compared with that of age-matched WT mice. Treatment of aorta and CC from Akita mice with an Arg inhibitor (BEC or ABH) reduced diabetes-induced elevation of Arg activity and restored endothelial and nitrergic function. Reduced levels of phospho-eNOS at Ser(1177) (in aorta and CC) and nNOS expression (in CC) were observed in Akita mice at 12 and 24 wks. Akita mice also had decreased NOS activity in aorta and CC at 12 and 24 wks that was restored by BEC treatment. Further, Akita mice exhibited moderately increased SBP at 24 wks and increased sensitivity to PE-induced contractions in aorta and sympathetic nerve stimulation in CC at 12 and 24 wks.
  
  
  CONCLUSIONS
  Over 24 wks of diabetes in Akita mice, both aortic and cavernosal tissues exhibited increased Arg activity/expression, contributing to impaired endothelial and nitrergic function and reduced NO production. Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse.
authors: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia, United States of America. hflorestoque@gru.edu
authors: Haroldo A
authors: HA
authors: Toque
authors: Kenia P
authors: KP
authors: Nunes
authors: Lin
authors: L
authors: Yao
authors: Zhimin
authors: Z
authors: Xu
authors: Dmitry
authors: D
authors: Kondrikov
authors: Yunchao
authors: Y
authors: Su
authors: R Clinton
authors: RC
authors: Webb
authors: Ruth B
authors: RB
authors: Caldwell
authors: R William
authors: RW
authors: Caldwell
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010413:Penis / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology
chemical_list: C425062:(2-boronoethyl)-cysteine; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase
references: Hypertension. 2004 Dec;44(6):935-43
references: 15492130
references: J Appl Physiol (1985). 2008 Nov;105(5):1632-42
references: 18719233
references: Diabetologia. 2004 Dec;47(12):2059-71
references: 15662548
references: J Sex Med. 2010 Dec;7(12):3857-67
references: 20807329
references: J Sex Med. 2005 May;2(3):347-55; discussion 355-7
references: 16422866
references: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9121-6
references: 15184671
references: Nat Struct Biol. 1999 Nov;6(11):1043-7
references: 10542097
references: Hypertension. 1995 May;25(5):1111-5
references: 7737724
references: Circulation. 2002 Apr 9;105(14):1656-62
references: 11940543
references: Clin Exp Pharmacol Physiol. 2007 Sep;34(9):906-11
references: 17645639
references: FASEB J. 2003 Dec;17(15):2328-30
references: 14563685
references: Biol Pharm Bull. 2006 Jun;29(6):1110-9
references: 16755002
references: Diabetes. 2003 Sep;52(9):2396-402
references: 12941781
references: J Urol. 2004 Jul;172(1):369-73
references: 15201813
references: Circulation. 2004 Dec 14;110(24):3708-14
references: 15569838
references: Circulation. 2002 Jul 23;106(4):466-72
references: 12135947
references: J Cardiovasc Pharmacol. 2010 Apr;55(4):308-16
references: 20422735
references: Cardiovasc Res. 2010 Jan 1;85(1):194-203
references: 19684035
references: Am J Physiol Endocrinol Metab. 2001 Jan;280(1):E75-82
references: 11120661
references: J Sex Med. 2010 Feb;7(2 Pt 1):758-68
references: 19912487
references: Diabetes. 2011 Nov;60(11):3015-22
references: 21926276
references: Mol Urol. 2001 Winter;5(4):189-97
references: 11790282
references: J Hypertens. 2005 May;23(5):971-8
references: 15834282
references: Mol Cell Biochem. 2009 Dec;332(1-2):95-102
references: 19543853
references: FASEB J. 2001 May;15(7):1264-6
references: 11344108
references: Gen Pharmacol. 2000 Dec;35(6):311-8
references: 11922961
references: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2035-42
references: 16794224
references: Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H283-91
references: 12793980
references: Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):218-23
references: 16373499
references: Biol Reprod. 2002 Jan;66(1):185-9
references: 11751281
references: Vascul Pharmacol. 2012 Nov-Dec;57(5-6):194-200
references: 22281732
references: Clin Exp Pharmacol Physiol. 2009 Aug;36(8):764-9
references: 19207718
references: J Clin Invest. 2001 Nov;108(9):1341-8
references: 11696579
references: Vascul Pharmacol. 2007 Nov-Dec;47(5-6):272-80
references: 17804300
references: Diabetes. 1997 May;46(5):887-94
references: 9133560
references: Circ Res. 2008 Apr 25;102(8):923-32
references: 18309100
references: J Androl. 2009 Jul-Aug;30(4):352-62
references: 19342700
references: J Sex Med. 2011 Mar;8(3):722-33
references: 21054801
references: J Hypertens. 2008 Jun;26(6):1110-8
references: 18475148
references: Int J Oncol. 2008 Feb;32(2):357-65
references: 18202758
references: Hypertension. 2006 Feb;47(2):245-51
references: 16380531
references: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9260-4
references: 11470919
references: Am J Physiol Renal Physiol. 2006 Jan;290(1):F214-22
references: 16118394
references: J Appl Physiol (1985). 2009 Oct;107(4):1249-57
references: 19661445
references: Am J Physiol Heart Circ Physiol. 2012 Jan 1;302(1):H159-66
references: 22058149
references: Am J Physiol Regul Integr Comp Physiol. 2003 Jan;284(1):R1-12
references: 12482742
references: Circ Res. 2008 Jan 4;102(1):95-102
references: 17967788
references: Biochem Biophys Res Commun. 2001 May 18;283(4):923-7
references: 11350073
references: J Mol Cell Cardiol. 2004 Aug;37(2):515-23
references: 15276021
references: Circulation. 2003 Oct 21;108(16):2000-6
references: 14517171
references: Endocrinology. 2009 Feb;150(2):849-61
references: 18845644
references: Br J Pharmacol. 2012 Jan;165(2):506-19
references: 21740411