The Effect of Soluble RAGE on Inhibition of Angiotensin II-Mediated Atherosclerosis in Apolipoprotein E Deficient Mice

BACKGROUND: The cross talk between RAGE and angiotensin II (AngII) activation may be important in the development of atherosclerosis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. In this study, we sought to determine the effect of sRAGE in inhibiting AngII-induced atherosclerosis in apolipoprotein E knockout mice (Apo E KO). METHODS AND RESULTS: 9 week old Apo E KO mice were infused subcutaneously with AngII (1 µg/min/kg) and saline for 4 weeks using osmotic mini-pumps. The mice were divided into 4 groups 1. saline infusion and saline injection; 2. saline infusion and sRAGE injection; 3. AngII infusion and saline injection; 4. AngII infusion and sRAGE injection. Saline or 0.5 µg, 1 µg, to 2 µg/day/mouse of sRAGE were injected intraperitoneally daily for 28 days. We showed that atherosclerotic plaque areas in the AngII-infused Apo E KO mice and markers of inflammation such as RAGE, ICAM-1, VCAM-1, and MCP-1 were increased in aorta compared to that of the Apo E KO mice. However, the treatment of 0.5 µg, 1 µg, and 2 µg of sRAGE in AngII group resulted in the dose-dependent decrease in atherosclerotic plaque area. We also demonstrated that sRAGE decreased RAGE expression level as well as inflammatory cytokines and cell adhesion molecules in AngII or HMGB1 treated-rat aorta vascular smooth muscle cells. CONCLUSION: The results demonstrated that partical blockade of RAGE activation by sRAGE prevent AngII -induced atherosclerosis. Therefore these results suggested that first, RAGE activation may be important in mediating AngII-induced atherogenesis, and second, AngII activation is a major pathway in the development of atherosclerosis. Taken together, results from this study may provide the basis for future anti- atherosclerotic drug development mediated through RAGE activation.ope

Protective effect of survivin in Doxorubicin-induced cell death in h9c2 cardiac myocytes.

BACKGROUND AND OBJECTIVES: Apoptosis has been known to be an important mechanism of doxorubicin-induced cardiotoxicity. Survivin, which belongs to the inhibitor of apoptosis protein family, is associated with apoptosis and alteration of the cardiac myocyte molecular pathways. Therefore, we investigated the anti-apoptotic effect and cellular mechanisms of survivin using a protein delivery system in a doxorubicin-induced cardiac myocyte injury model. MATERIALS AND METHODS: We constructed a recombinant survivin which was fused to the protein transduction domain derived from HIV-TAT protein. In cultured H9c2 cardiac myocytes, TAT-survivin (1 µM) was added for 1 hour prior to doxorubicin (1 µM) treatment for 24 hours. Cell viability and apoptosis were evaluated by 2-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, caspase-3 activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay. We measured the expression levels of several apoptosis-related signal proteins. RESULTS: The survivin level was significantly reduced in a dose dependent manner up to 1 µM of doxorubicin in concentration. Purified recombinant TAT-survivin protein was efficiently delivered to H9c2 cardiac myocytes, and its transduction showed an anti-apoptotic effect, demonstrated by reduced caspase-3 activity and the apoptotic index, concomitantly with increased cell viability against doxorubicin injury. The phosphorylation of p38 mitogen-activated protein (MAP) kinase and the release of Smac from mitochondria were suppressed and the expression levels of Bcl-2 and cAMP response element-binding protein (CREB), the transcription factor of Bcl-2, were recovered following TAT-survivin transduction, indicating that survivin had an anti-apoptotic effect against doxorubicin injury. CONCLUSION: Our results suggest that survivin has a potentially cytoprotective effect against doxorubicin-induced cardiac myocyte apoptosis through mechanisms that involve a decrease in the phosphorylation of p38 MAP kinase, mitochondrial Smac release, and increased expression of Bcl-2 and CREB.ope

C-Reactive Protein Inhibits Survivin Expression via Akt/mTOR Pathway Downregulation by PTEN Expression in Cardiac Myocytes.

C-reactive protein (CRP) is one of the most important biomarkers for arteriosclerosis and cardiovascular disease. Recent studies have shown that CRP affects cell cycle and inflammatory process in cardiac myocytes. Survivin is also involved in cardiac myocytes replication and apoptosis. Reduction of survivin expression is associated with less favorable cardiac remodeling in animal models. However, the effect of CRP on survivin expression and its cellular mechanism has not yet been studied. We demonstrated that treatment of CRP resulted in a significant decrease of survivin protein expression in a concentration-dependent manner in cardiac myocytes. The upstream signaling proteins of survivin, such as Akt, mTOR and p70S6K, were also downregulated by CRP treatment. In addition, CRP increased the protein and mRNA levels of PTEN. The siRNA transfection or specific inhibitor treatment for PTEN restored the CRP-induced downregulation of Akt/mTOR/p70S6K pathway and survivin protein expression. Moreover, pretreatment with a specific p53 inhibitor decreased the CRP-induced PTEN expression. ERK-specific inhibitor also blocked the p53 phosphorylation and PTEN expression induced by CRP. Our study provides a novel insight into CRP-induced downregulation of survivin protein expression in cardiac myocytes through mechanisms that involved in downregulation of Akt/mTOR/p70S6K pathway by expression of PTEN.ope

An Impossible Other -A Critique of Jean-Luc Marion`s Thesis on the Alterity of the Ego-

이 글은 프랑스의 데카르트 연구자인 장－뤽 마리옹의 에고의 타자성론을 비판적으로 고찰하는 것을 목적으로 삼고 있다. 이를 위해 이 글에서는 마리옹의 두 개의 논문을 중심적으로 다루고 있다. 마리옹의 에 고의 타자성론은 데카르트의 에고는 근원적으로 타인과의 대화라는 틀 속 에 위치하고 있으며, 이 때문에 데카르트 철학은 탈근대성으로 진입하는 하나의 입구가 될 수 있다는 주장으로 요약된다. 하지만 그가 주장하는 에 고의 타자성론은 (1) 텍스트상의 전거가 취약할 뿐만 아니라 (2) ego sum, ego existo에 대한 해석에서 코기토의 경험의 첨예함을 약화시키고 있다. 이에 따라 그의 에고의 타자성은 타자성을 존중한다는 주장에도 불구하고 결국 타자성을 폐쇄된 공간 속에서의 타자성으로 만들고 만

(A)Relationalist interpretation on the philosophy of Spinoza

학위논문(박사)--서울대학교 대학원 :철학과 서양철학전공,2006.Docto

The Concept of Causa sui in Spinoza

This paper aims to elucidate the meaning of causa sui in Spinozas philosophy. The first philosopher who used this concept in a positive way was not Spinoza but Descartes. However, Spinoza was the first and the only philosopher who separated its use from the discourse of proving the existence of God, and so detheologized it. The term causa sui in the first part of Ethics signifies three things: First, it criticizes the transcendence of God; second, it provides the basis for immanent causality; third, it shows the non-reflexiveness of God or Nature

스피노자 철학에 대한 관계론적 해석

다른 모든 철학들과 마찬가지로 스피노자의 철학 역시 해석의 역사, 그 영향의 역사로부터 자유롭지 못하다. 어떤 의미에서 스피노자의 철학은 그 해석의 역사 영향사 안에서만 식별되고 존립할 수 있다고 할 수 있다. 따라서 스피노자 철학에 대한 연구, 더욱이 그의 체계를 포괄적으로 재구성해보려고 시도하는 연구는 반드시 그 해석의 역사에 대한 재해석과 평가를 포함해야 한다. 그렇지 않을 경우, 그 연구가 주장하는 관점의 독자성은 사실은 주관적인 오해와 착각에 머무르거나 아니면 이전에 제시되었던 이러저러한 해석을 진부하게 되풀이하는 함정에서 벗어나기 어려울 것이다. 우리가 이 논문에서 스피노자 철학에 대한 관계론적 해석을 제안하면서, 범신론적 해석과 역량론적 해석이라는 스피노자 철학에 대한 두 가지 주요한 해석의 흐름에 대한 비판적 분석을 우리 논문의 본질적인 일부로 삼은 이유가 바로 여기에 있다