239 802

Cited 0 times in

Possible role of HMG CoA reductase inhibitor on the oxidative stress induced by advanced glycation endproducts (AGEs) in vascular smooth muscle cell of diabetic vasculopathy

Other Titles
 당뇨성 혈관병증에서 혈관 
Authors
 윤세정 
Department
 Dept. of Internal Medicine (내과학교실) 
Issue Date
2008
Description
Dept. of Medicine/박사
Abstract
[한글]

최근 HMG CoA reductase inhibitor의 항산화 작용은 그 다양한 효과 중의 한가지로 알려져 있으며 특히 당뇨성 혈관병리에 있어서 매우 중요하다. Advanced glycation endproducts (AGEs)에 의한 reactive oxygen species (ROS)의 발생과 평활근 세포 증식이 당뇨성 혈관병증의 중요한 기전으로 부각되고 있으나 AGEs에 대한 HMG CoA reductase inhibitor의 항산화 작용에 대해서는 아직 자세히 알려진 바가 없다. 이에 본 연구에서는 HMG CoA reductase inhibitor가 AGEs로 인해 증가된 혈관 평활근 세포내 산화 스트레스를 감소시킬 것이라는 가설을 세우고 ROS로 인해 유발된 세포내 전달 기전에 영향을 미치는 HMG CoA reductase inhibitor의 역할에 대한 가능한 기전을 분석하고자 하였다. AGEs를 처리하였을 때 용량에 비례하여 백서의 혈관 평활근 세포의 증식과 ROS의 증가를 보였으며 NFκB, phosphorylated ERKs, phosphorylated p38, COX-2과 c-jun의 발현이 증가되었다. 대조군(HMG CoA reductase inhibitor 처리하지 않은)과 비교해서 HMG CoA reductase inhibitor를 처리한 군은 AGEs로 인한 혈관 평활근 세포의 증식과 ROS 생성, 그리고 NFκB, phosphorylated ERKs, phosphorylated p38, COX-2과 c-jun의 발현이 용량에 비례하여 억제되었다. 풍선으로 손상을 준 후 그렇지 않은 군보다 백서의 총경동맥 신생 내막의 형성이 증가되었으나 HMG CoA reductase inhibitors로 치료을 한 군에서 신생 내막의 형성이 억제된 것을 볼 수 있었다. RAGE (AGEs에 대한 수용체)에 대한 siRNA를 사용했을 때 HMG CoA reductase inhibitor를 사용한 군과 ERK의 발현에는 차이가 없었다. 본 연구에서 AGEs는 혈관 평활근 세포 증식과 ROS 증가에 중요한 역할을 하는 것을 보여주고 있으며 HMG CoA reductase inhibitor는 AGEs로 인한 혈관 평활근 세포의 증식, ROS 생성 그리고 MAPK의 활성도를 억제시키는 것을 알 수 있다. 결론적으로, ROS 생성과 MAPK의 활성화는 AGEs로 인한 당뇨성 혈관병리의 가능한 기전으로 HMG CoA reductase inhibitor는 이러한 AGEs로 인한 당뇨성 동맥경화의 치료에 있어서 중요한 역할을 할 것이라는 결론을 내릴 수 있다.



[영문]Antioxidative effect of HMG CoA reductase inhibitor has recently been noted as one of their pleiotrophic effects and is especially important in the aspects of diabetic vasculopathy. Advanced glycation endproducts (AGEs) induced smooth muscle cell proliferation and formation of reactive oxygen species (ROS) are emerging as one of the important mechanism of diabetic vasculopathy, but little is known about antioxidative action of HMG CoA reductase inhibitor on AGEs. We hypothesized that HMG CoA reductase inhibitor might reduce the AGEs-induced intracellular ROS of VSMCs. In this study, we analyze the possible mechanism of action of HMG CoA reductase inhibitor in the AGEs-induced cellular signaling. Rat aortic smooth muscle cell (RASMC) culture was done using the different levels of AGEs stimulation in the presence or absence of HMG CoA reductase inhibitor. Increasing concentration of AGEs stimulation was associated with increased VSMC proliferation and with increased ROS formation. Increased NFκB, phosphorylated ERKs, phosphorylated p38, COX-2 and c-jun by AGEs stimulation were noted. Comparing with the control cells (without HMG CoA reductase inhibitor treatment), HMG CoA reductase inhibitor inhibited AGEs-stimulated VSMC proliferation in dose dependent manners. HMG CoA reductase inhibitor also inhibited intracellular ROS formation and the expression of NFκB, phosphorylated ERKs, phosphorylated p38, COX-2 and c-jun induced by AGEs. Neointimal formation after balloon injury was much thicker in streptozocin-indcued diabetic S-D rats than in sham-treated group, but less neointimal growth was observed in those treated with HMG CoA reductase inhibitor after balloon injury. siRNA-mediated silencing of RAGE (receptor for AGEs) expression had no effect on the change of ERK mediated by HMG CoA reductase inhibitor. In vitro and in vivo data suggest that AGEs may play a key role in VSMC proliferation and increase the oxidative stress. HMG CoA reductase inhibitor inhibited the AGEs-induced proliferation of VSMCs, ROS formation and activity of the MAPK. Activation of MAPK system and increased ROS formation may be the possible mechanism of diabetic vasculopathy induced by AGEs and HMG CoA reductase inhibitor may play a key role in treatment of AGEs-induced diabetic atherosclerosis.
Files in This Item:
T010198.pdf Download
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 3. Dissertation
Yonsei Authors
Yoon, Se Jung(윤세정)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/124007
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links