title: Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse.
abstract: OBJECTIVE
  To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress.
  
  
  METHODS
  The study was performed using diabetic apolipoprotein E/GPx1 (ApoE(-/-)GPx1(-/-))-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks.
  
  
  RESULTS
  Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways.
  
  
  CONCLUSIONS
  Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.
authors.affiliation: Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Phyllis
authors.initials: P
authors.lastname: Chew
authors.forename: Derek Y C
authors.initials: DY
authors.lastname: Yuen
authors.forename: Nada
authors.initials: N
authors.lastname: Stefanovic
authors.forename: Josefa
authors.initials: J
authors.lastname: Pete
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.forename: Karin A
authors.initials: KA
authors.lastname: Jandeleit-Dahm
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.forename: Franklin
authors.initials: F
authors.lastname: Rosenfeldt
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Judy B
authors.initials: JB
authors.lastname: de Haan
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000517:prevention & control*; D001393:Azoles / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D005979:Glutathione Peroxidase / Q000172:deficiency*; D054833:Isoindoles; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D001057:Apolipoproteins E; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C002744:3-nitrotyrosine; C042986:ebselen; D014443:Tyrosine; D005979:Glutathione Peroxidase; C027576:4-hydroxy-2-nonenal; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
references.citation: Can J Vet Res. 1986 Jul;50(3):297-306
references.pmid: 3527390
references.citation: J Nutr. 2001 Dec;131(12):3208-11
references.pmid: 11739867
references.citation: Curr Vasc Pharmacol. 2004 Oct;2(4):335-41
references.pmid: 15320813
references.citation: Diabetes. 2004 Sep;53(9):2455-60
references.pmid: 15331559
references.citation: Free Radic Biol Med. 1993 Mar;14(3):313-23
references.pmid: 8458589
references.citation: JAMA. 2005 Jul 6;294(1):56-65
references.pmid: 15998891
references.citation: Diabetes Care. 2000 Jan;23(1):30-3
references.pmid: 10857964
references.citation: J Am Soc Nephrol. 2005 Jan;16(1):27-45
references.pmid: 15563560
references.citation: Kidney Int. 2003 Sep;64(3):817-28
references.pmid: 12911531
references.citation: J Clin Invest. 1997 Dec 15;100(12):2995-3004
references.pmid: 9399945
references.citation: Kidney Int. 1989 May;35(5):1203-11
references.pmid: 2671464
references.citation: J Cell Biol. 1980 Jun;85(3):597-616
references.pmid: 6993495
references.citation: Circulation. 2007 Apr 24;115(16):2178-87
references.pmid: 17420349
references.citation: Diabetologia. 2010 Jan;53(1):192-203
references.pmid: 19862499
references.citation: Drug Discov Today. 2004 Jul 1;9(13):557-66
references.pmid: 15203091
references.citation: Coron Artery Dis. 2003 Apr;14(2):149-53
references.pmid: 12655278
references.citation: Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):12-22
references.pmid: 14604830
references.citation: J Nephrol. 2009 Jan-Feb;22(1):39-45
references.pmid: 19229817
references.citation: Pediatr Nephrol. 2009 Dec;24(12):2309-19
references.pmid: 19421784
references.citation: Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):823-30
references.pmid: 19325139
references.citation: Stroke. 1998 Jan;29(1):12-7
references.pmid: 9445321
references.citation: Adv Pharmacol. 1997;38:229-46
references.pmid: 8895811
references.citation: Redox Rep. 2003;8(2):69-79
references.pmid: 12804009
references.citation: J Biol Chem. 1998 Aug 28;273(35):22528-36
references.pmid: 9712879
references.citation: Circ Res. 2004 Feb 20;94(3):377-84
references.pmid: 14670841
references.citation: J Am Soc Nephrol. 2004 Sep;15(9):2391-403
references.pmid: 15339988
references.citation: Eur J Pharmacol. 2004 Feb 6;485(1-3):127-35
references.pmid: 14757132
references.citation: Annu Rev Nutr. 1999;19:1-16
references.pmid: 10448514
references.citation: Am J Physiol Renal Physiol. 2005 Sep;289(3):F544-51
references.pmid: 15827346
references.citation: Drug Metab Rev. 2000 Aug-Nov;32(3-4):377-85
references.pmid: 11139135
references.citation: J Biol Chem. 1997 Oct 31;272(44):27812-7
references.pmid: 9346926
references.citation: Nature. 2001 Dec 13;414(6865):813-20
references.pmid: 11742414
references.citation: Biol Res Nurs. 2004 Jul;6(1):37-45
references.pmid: 15186706
references.citation: J Am Soc Nephrol. 2004 Aug;15(8):2125-38
references.pmid: 15284298
references.citation: N Engl J Med. 1998 Jul 23;339(4):229-34
references.pmid: 9673301
references.citation: J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S241-5
references.pmid: 12874439
references.citation: Biomed Pharmacother. 2005 Aug;59(7):365-73
references.pmid: 16081237
references.citation: Kidney Int. 2001 Apr;59(4):1342-53
references.pmid: 11260395
references.citation: JAMA. 2008 Nov 12;300(18):2123-33
references.pmid: 18997197
references.citation: Blood Press. 2005;14(6):366-72
references.pmid: 16403691
references.citation: Chemistry. 2007;13(16):4594-601
references.pmid: 17299817
references.citation: J Biol Chem. 2001 Jun 15;276(24):20831-8
references.pmid: 11259420
references.citation: Circulation. 2003 Oct 28;108(17):2154-69
references.pmid: 14581387
references.citation: N Engl J Med. 2003 Oct 23;349(17):1605-13
references.pmid: 14573732