title: Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy.
abstract: Advanced glycation endproducts (AGEs) have been reported to play a role in neointimal formation and increase the rate of in-stent restenosis (ISR) in the diabetic coronary artery disease patients treated with stents, but the potential pathogenic mechanisms of AGEs in vascular smooth muscle cell proliferation remain unclear. We sought to determine the AGEs related pathobiological mechanism of diabetic vasculopathy. Rat aortic smooth muscle cell (RAoSMC) culture was done with different concentrations of AGEs and proliferation was assessed. Immunohistochemistry for receptor of AGEs (RAGE) was performed with human carotid atheroma. Western blotting was performed to assess the activation of MAP kinase system in the cultured RAoSMC. AGEs increased RAoSMC proliferation and were associated with increased phosphorylation of ERK and p38 kinase by time and dose dependent manner. The MAP kinase activity was decreased by RNA interference for RAGE. AGEs stimulation increased reactive oxygen species (ROS) generation in cultured RAoSMC. From this study it is concluded that AGEs played a key role in RAoSMC proliferation via MAP kinase dependent pathways. Activation of vascular smooth muscle cell (VSMC) proliferation by MAP kinase system and increased formation of ROS may be the possible mechanisms of AGEs induced diabetic vasculopathy.
authors.affiliation: Division of Cardiology, Yong Dong Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Korea.
authors.forename: Young Won
authors.initials: YW
authors.lastname: Yoon
authors.forename: Tae Soo
authors.initials: TS
authors.lastname: Kang
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Lee
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
authors.forename: Ji-Hyuck
authors.initials: JH
authors.lastname: Rhee
authors.forename: Pil-Ki
authors.initials: PK
authors.lastname: Min
authors.forename: Bum-Kee
authors.initials: BK
authors.lastname: Hong
authors.forename: Se-Joong
authors.initials: SJ
authors.lastname: Rim
authors.forename: Hyuck Moon
authors.initials: HM
authors.lastname: Kwon
mesh_terms: D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D048049:Extracellular Signal-Regulated MAP Kinases
references.citation: Circulation. 1990 Jul;82(1):27-36
references.pmid: 2194696
references.citation: Eur J Pharmacol. 2004 Jan 26;484(2-3):119-25
references.pmid: 14744595
references.citation: Diabetes. 1997 Mar;46(3):463-72
references.pmid: 9032104
references.citation: Annu Rev Med. 1995;46:223-34
references.pmid: 7598459
references.citation: Circulation. 2004 Feb 24;109(7):867-73
references.pmid: 14757691
references.citation: Am J Pathol. 1995 Mar;146(3):688-94
references.pmid: 7887450
references.citation: Exp Mol Med. 2006 Oct 31;38(5):525-34
references.pmid: 17079869
references.citation: N Engl J Med. 1988 May 19;318(20):1315-21
references.pmid: 3283558
references.citation: Biochem Biophys Res Commun. 1996 May 24;222(3):700-5
references.pmid: 8651908
references.citation: Am J Physiol Endocrinol Metab. 2001 May;280(5):E685-94
references.pmid: 11287350
references.citation: N Engl J Med. 1993 Sep 30;329(14):977-86
references.pmid: 8366922
references.citation: J Biol Chem. 1999 Jul 9;274(28):19919-24
references.pmid: 10391939
references.citation: Exp Mol Med. 2006 Apr 30;38(2):153-61
references.pmid: 16672769
references.citation: J Steroid Biochem Mol Biol. 2002 Jan;80(1):85-90
references.pmid: 11867267
references.citation: FASEB J. 2004 Jan;18(1):176-8
references.pmid: 12709399
references.citation: J Am Coll Cardiol. 1998 Jan;31(1):224-30
references.pmid: 9426044
references.citation: Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2027-33
references.pmid: 14500292
references.citation: Lab Invest. 1994 Feb;70(2):138-51
references.pmid: 8139257
references.citation: Yonsei Med J. 2005 Feb 28;46(1):78-85
references.pmid: 15744809
references.citation: Eur J Clin Invest. 1997 Feb;27(2):97-108
references.pmid: 9061302
references.citation: Endocrinol Metab Clin North Am. 1996 Jun;25(2):255-70
references.pmid: 8799700
references.citation: J Clin Invest. 2003 Apr;111(7):959-72
references.pmid: 12671045
references.citation: Circulation. 2001 Jun 19;103(24):2980-6
references.pmid: 11413090
references.citation: JAMA. 1979 May 11;241(19):2035-8
references.pmid: 430798
references.citation: Life Sci. 2007 Feb 20;80(11):1051-6
references.pmid: 17174344
references.citation: J Biol Chem. 1997 Jul 11;272(28):17810-4
references.pmid: 9211935
references.citation: Circulation. 1997 Sep 2;96(5):1454-60
references.pmid: 9315531
references.citation: Diabetes. 1997 Sep;46(9):1481-90
references.pmid: 9287050
references.citation: Circulation. 2003 May 6;107(17):2238-43
references.pmid: 12719284
references.citation: J Clin Invest. 1996 Sep 1;98(5):1088-94
references.pmid: 8787669
references.citation: Am J Pathol. 1993 Dec;143(6):1699-712
references.pmid: 8256857