Exp Mol Med.  2008 Aug;40(4):398-406. 10.3858/emm.2008.40.4.398.

Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy

• Yoon YW
• Kang TS
• Lee BK
• Chang W
• Hwang KC
• Rhee JH
• Min PK
• Hong BK
• Rim SJ
• Kwon HM

• KMID: 1094119
• DOI: http://doi.org/10.3858/emm.2008.40.4.398

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.

Keyword

therosclerosis; blood vessels; diabetes mellitus; glycation end products, advanced; mitogen-activated protein kinases

MeSH Terms

Animals
Carotid Artery Diseases/metabolism/pathology
Cell Proliferation/drug effects
Cells, Cultured
Diabetic Angiopathies/*etiology/metabolism/pathology
Extracellular Signal-Regulated MAP Kinases/metabolism
Glycosylation End Products, Advanced/adverse
Humans
MAP Kinase Signaling System/drug effects/*physiology
Phosphorylation/drug effects
RNA, Small Interfering/pharmacology
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species/metabolism
Receptors, Immunologic/antagonists & inhibitors/metabolism