Exp Mol Med.  2009 Nov;41(11):802-811. 10.3858/emm.2009.41.11.086.

Potential role of HMG CoA reductase inhibitor on oxidative stress induced by advanced glycation endproducts in vascular smooth muscle cells of diabetic vasculopathy

• Yoon SJ
• Yoon YW
• Lee BK
• Kwon HM
• Hwang KC
• Kim M
• Chang W
• Hong BK
• Lee YH
• Park SJ
• Min PK
• Rim SJ

• KMID: 1122281
• DOI: http://doi.org/10.3858/emm.2009.41.11.086

Abstract

Advanced glycation endproducts (AGEs)-induced vascular smooth muscle cell (VSMCs) proliferation and formation of reactive oxygen species (ROS) are emerging as one of the important mechanisms of diabetic vasculopathy but little is known about the antioxidative action of HMG CoA reductase inhibitor (statin) on AGEs. We hypothesized that statin might reduce AGEs-induced intracellular ROS of VSMCs and analyzed the possible mechanism of action of statin in AGEs-induced cellular signaling. Aortic smooth muscle cell of Sprague-Dawley rat (RASMC) culture was done using the different levels of AGEs stimulation in the presence or absence of statin. The proliferation of RASMC, ROS formation and cellular signaling was evaluated and neointimal formation after balloon injury in diabetic rats was analyzed. Increasing concentration of AGEs stimulation was associated with increased RASMC proliferation and increased ROS formation and they were decreased with statin in a dose-dependent manner. Increased NF-kappaB p65, phosphorylated ERK, phosphorylated p38 MAPK, cyclooxygenase-2, and c-jun by AGEs stimulation were noted and their expression was inhibited by statin. Neointimal formation after balloon injury was much thicker in diabetic rats than the sham-treated group but less neointimal growth was observed in those treated with statin after balloon injury. Increased ROS formation, subsequent activation of MAPK system and increased VSMC proliferation may be possible mechanisms of diabetic vasculopathy induced by AGEs and statin may play a key role in the treatment of AGEs-induced diabetic atherosclerosis.

Keyword

cyclooxygenase 2; diabetes mellitus; extracellular signal-regulated MAP kinases; hydroxymethylglutaryl-CoA reductase inhibitors; muscle, smooth, vascular; NFkappaB; p38 mitogen-activated protein kinases; proto-oncogene proteins c-jun; reactive oxygen species

MeSH Terms

Animals
Aorta/metabolism/pathology
Cell Proliferation/drug effects
Cyclooxygenase 2/metabolism
Diabetes Mellitus, Experimental/drug therapy/metabolism/pathology
Diabetic Angiopathies/*drug therapy/*metabolism/pathology
Glycosylation End Products, Advanced/*metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology/therapeutic use
Male
Myocytes, Smooth Muscle/*metabolism/pathology
Oxidative Stress/*drug effects
Proto-Oncogene Proteins c-jun/metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species/metabolism
Signal Transduction/drug effects
Simvastatin/*pharmacology/therapeutic use
Transcription Factor RelA/metabolism
p38 Mitogen-Activated Protein Kinases/metabolism