title: Vascular endothelial growth factor inhibition by dRK6 causes endothelial apoptosis, fibrosis, and inflammation in the heart via the Akt/eNOS axis in db/db mice.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF), which is associated with the stimulation of angiogenesis and collateral vessel synthase, is one of the crucial factors involved in cardiac remodeling in type 2 diabetes.
  
  
  METHODS
  We investigated VEGF inhibition by dRK6 on the heart in an animal model of type 2 diabetes. Male db/db and db/m mice either were treated with dRK6 starting at 7 weeks of age for 12 weeks (db/db-dRK6 and db/m-dRK6) or were untreated.
  
  
  RESULTS
  Cardiac dysfunction and hypertrophy were noted by echocardiogram and molecular markers in the db/db-dRK6 mice. The presence of diabetes significantly suppressed the expression of VEGF receptor (VEGFR)-1 and VEGFR-2, phospho-Akt, and phospho-endothelial nitric oxide synthase (eNOS) in the heart. In db/db-dRK6 mice, dRK6 completely inhibited VEGFR-2, phospho-Akt, and phospho-eNOS expression, whereas no effect on VEGFR-1 was observed. Cardiac fibrosis, microvascular scarcity associated with an increase in apoptotic endothelial cells, and inflammation were prominent, as well as increase in antiangiogenic growth factors. Cardiac 8-hydroxy-deoxyguanine and hypoxia-inducible factor-1alpha expression were significantly increased. No such changes were found in the other groups, including the db/m-dRK6 mice. The number of apoptotic human umbilical vein endothelial cells was increased by dRK6 in a dose-dependent manner only at high glucose concentrations, and this was associated with a decrease in phospho-Akt and phospho-eNOS related to oxidative stress.
  
  
  CONCLUSIONS
  Our results demonstrated that systemic blockade of VEGF by dRK6 had deleterious effects on the heart in an animal model of type 2 diabetes; dRK6 induced downregulation of the VEGFR-2 and Akt-eNOS axis and enhancement of oxidative stress.
authors.affiliation: Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
authors.forename: Hyung Wook
authors.initials: HW
authors.lastname: Kim
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Lim
authors.forename: Ki Dong
authors.initials: KD
authors.lastname: Yoo
authors.forename: Sungjin
authors.initials: S
authors.lastname: Chung
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Shin
authors.forename: Hyun Wha
authors.initials: HW
authors.lastname: Chung
authors.forename: Sang Ju
authors.initials: SJ
authors.lastname: Lee
authors.forename: Chi-Bom
authors.initials: CB
authors.lastname: Chae
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000473:pathology / Q000517:prevention & control*; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019700:Thrombospondin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D009842:Oligopeptides; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; C501225:arginyl-arginyl-lysyl-arginyl-arginyl-arginine; D018799:Intercellular Adhesion Molecule-1; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D003849:Deoxyguanosine
references.citation: Circulation. 2003 Aug 12;108(6):754-9
references.pmid: 12885755
references.citation: Diabet Med. 2009 Mar;26(3):247-52
references.pmid: 19317819
references.citation: J Biol Chem. 2000 May 5;275(18):13588-96
references.pmid: 10788475
references.citation: Circulation. 2005 Apr 26;111(16):2073-85
references.pmid: 15851615
references.citation: Circ Res. 2004 Jan 9;94(1):7-16
references.pmid: 14715531
references.citation: J Biol Chem. 1996 Dec 20;271(51):32529-37
references.pmid: 8955077
references.citation: J Biol Chem. 2000 Jul 14;275(28):21695-702
references.pmid: 10777488
references.citation: Novartis Found Symp. 2006;272:2-8; discussion 8-14, 33-6
references.pmid: 16686426
references.citation: Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1104-13
references.pmid: 11052966
references.citation: Br J Cancer. 2007 Jun 18;96(12):1788-95
references.pmid: 17519900
references.citation: Circ Res. 2000 Dec 8;87(12):1123-32
references.pmid: 11110769
references.citation: Metabolism. 1998 Jan;47(1):27-30
references.pmid: 9440473
references.citation: Clin Sci (Lond). 2002 Feb;102(2):187-94
references.pmid: 11834138
references.citation: Circulation. 2002 Oct 1;106(14):1840-6
references.pmid: 12356639
references.citation: Circulation. 2004 Jun 22;109(24):3042-9
references.pmid: 15184284
references.citation: J Immunol. 2005 May 1;174(9):5846-55
references.pmid: 15843589
references.citation: Am J Pathol. 1999 Feb;154(2):355-63
references.pmid: 10027394
references.citation: Drugs. 2005;65(1):31-74
references.pmid: 15610050
references.citation: Can J Physiol Pharmacol. 2003 Jun;81(6):622-34
references.pmid: 12839273
references.citation: Diabet Med. 2001 May;18(5):423-4
references.pmid: 11472458
references.citation: Kidney Int. 2004 Jun;65(6):2003-17
references.pmid: 15149314
references.citation: Mol Cell Biochem. 1995 Jun 7-21;147(1-2):29-34
references.pmid: 7494551
references.citation: Cardiovasc Res. 2008 Feb 1;77(3):463-70
references.pmid: 18006459
references.citation: Circulation. 2002 Jan 22;105(3):373-9
references.pmid: 11804995
references.citation: J Am Coll Cardiol. 2000 Jan;35(1):19-28
references.pmid: 10636254
references.citation: Diabetes Care. 1990 Nov;13(11):1169-79
references.pmid: 2261838
references.citation: Circ Res. 2006 Mar 17;98(5):596-605
references.pmid: 16543510
references.citation: Am J Cardiol. 2004 Apr 22;93(8A):13A-16A
references.pmid: 15094099
references.citation: J Am Coll Cardiol. 2003 Aug 6;42(3):454-7
references.pmid: 12906971
references.citation: Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1744-51
references.pmid: 15964918
references.citation: Semin Oncol. 2006 Oct;33(5 Suppl 10):S26-34
references.pmid: 17145522
references.citation: Diabet Med. 2000 Sep;17(9):650-6
references.pmid: 11051284
references.citation: Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H560-76
references.pmid: 16172168
references.citation: Angiogenesis. 2002;5(4):237-56
references.pmid: 12906317
references.citation: Br J Pharmacol. 2007 Apr;150(7):833-8
references.pmid: 17293884
references.citation: Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H547-59
references.pmid: 16172161
references.citation: Endocr Rev. 2004 Aug;25(4):543-67
references.pmid: 15294881
references.citation: Nat Med. 1999 May;5(5):495-502
references.pmid: 10229225
references.citation: Eur J Pharmacol. 2006 Aug 7;542(1-3):184-5
references.pmid: 16906650
references.citation: Am J Cardiovasc Drugs. 2007;7(6):393-8
references.pmid: 18076206
references.citation: Diabetologia. 2001 Jun;44(6):674-92
references.pmid: 11440360
references.citation: Mol Cell Biochem. 2004 Jun;261(1-2):187-91
references.pmid: 15362503
references.citation: Diabetes. 1993 Jun;42(6):801-13
references.pmid: 8495803
references.citation: Am J Physiol Heart Circ Physiol. 2002 Sep;283(3):H976-82
references.pmid: 12181126