Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy.
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.
Yoon
Young Won
YW
Division of Cardiology, Yong Dong Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Korea.
Kang
Tae Soo
TS
Lee
Byoung Kwon
BK
Chang
Woochul
W
Hwang
Ki-Chul
KC
Rhee
Ji-Hyuck
JH
Min
Pil-Ki
PK
Hong
Bum-Kee
BK
Rim
Se-Joong
SJ
Kwon
Hyuck Moon
HM
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
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
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