Effect of S-adenosylmethionine on neointimal formation after balloon injury in obese diabetic rats.
OBJECTIVE
The association between hyperhomocysteinaemia and cardiovascular disease has been attributed to low levels of S-adenosylmethionine (SAM), a metabolic intermediate of homocysteine. However, the role of SAM in the development of restenosis has not been explored. Therefore, we investigated the effects of SAM on neointimal formation after balloon injury in obese diabetic rats and cultured cells.


RESULTS
Otsuka Long-Evans Tokushima fatty rats were divided into the following three groups: control (normal saline); SAM15; and SAM30 (15 and 30 mg/kg per day, respectively; n = 10 per group). SAM was administered orally from 1 week before carotid injury to 2 weeks thereafter. SAM treatment for 3 weeks caused a significant dose-dependent reduction in the intima-to-media ratio. SAM treatment significantly reduced the proliferation of vascular smooth muscle cells (VSMCs) and induced more apoptosis than was observed in the control group. This effect was accompanied by reduced circulating levels of high-sensitivity C-reactive protein and monocyte chemoattractant protein-1, reduced urine 8-hydroxy-2'-deoxyguanosine (8-OHdG), and increased adiponectin. Intima-to-media ratio correlated significantly with the levels of inflammatory markers, adiponectin, and 8-OHdG. In vitro experiments demonstrated that VSMC proliferation and migration and the adhesion of monocytes decreased in response to SAM. SAM treatment also reduced tumour necrosis factor-α-induced reactive oxygen species and tunicamycin-induced GRP78 expression in VSMCs.


CONCLUSIONS
These findings suggest that SAM exerts protective effects against restenosis after balloon injury in a rat model of type 2 diabetes by reducing the proliferation and inducing the apoptosis of VSMCs, modifying the inflammatory processes and reducing oxidative and endoplasmic reticulum stresses.
Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, Korea 110-744.
Soo
S
Lim
Min Kyong
MK
Moon
Hayley
H
Shin
Tae Hyuk
TH
Kim
Bong Jun
BJ
Cho
Min
M
Kim
Ho Seon
HS
Park
Sung Hee
SH
Choi
Seong-Hee
SH
Ko
Myung Hee
MH
Chung
In Kyu
IK
Lee
Hak Chul
HC
Jang
Young-Bum
YB
Kim
Kyong Soo
KS
Park
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007333:Insulin Resistance; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D058426:Neointima / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D020334:Rats, Inbred OLETF; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D014657:Vasculitis / Q000150:complications / Q000188:drug therapy / Q000276:immunology
D015415:Biomarkers; D012436:S-Adenosylmethionine