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Proteomic analysis of differential protein expression in atherosclerosis and regulatory role of human LZIP in development of atherosclerosis

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dc.descriptionDept. of Biomedical Laboratory Science/박사-
dc.description.abstract[한글]동맥경화에서 특이적으로 발현하는 단백질을 발굴하기 위하여 동맥경화 환자의 병변 조직과 정상 조직을 채취한 후, 프로테오믹스를 이용하여 특이단백질을 분석하였다. 2 DE 기법을 이용하여 분석한 결과, 발현 차이가 나는 39개의 단백질을 발굴하여 MALDI-TOF 을 이용하여 peptide mapping을 하였고, MS-FIT database를 이용하여 단백질을 분석하였다. 39개의 단백질 중 27개의 단백질을 동정 하였으며, 이 단백질들은 동맥경화 발병 과정에서 중요한 역할을 하는 단백질들이었다. 특히, 세포 내 칼슘 매개 진행과정, 혈관 연근육 세포의 유주 현상, MMP 물질의 활성 및 염증관여 사이토카인 전구체들의 조절 등에 관여하는 단백질들이 발견되었다.케모카인 MCP-1과 그 수용체 CCR2는 동맥경화의 발병 단계에서 단핵구를 혈관벽으로 유주시키는 중요한 역할을 한다. LZIP은 백혈구의 유주 활성을 조절하는 새로운 전사인자이다. LZIP의 동맥경화 발병과정에서의 역할을 조사하기 위하여, LZIP에 의하여 발현되는 케모카인과 수용체들을 RNase protection 법을 이용하여 검색하였다. 단핵구에서 LZIP은 동맥경화에서 중요한 MCP-1, Lkn-1 등의 케모카인과 CCR1, CCR2 등의 수용체 발현을 mRNA와 단백질 수준에서 증가시켰다. LZIP은 MCP-1에 의한 화학주성을 증가시켰고, 동맥경화의 진행과정 중 형성되는 거품세포에서 과 발현되어 있었다. siRNA LZIP은 거품세포의 형성을 억제하여 LZIP이 거품세포 형성에 관여함을 관찰하였다. 또한, LZIP은 CCR2 촉진 염기서열의 C/EBP 요소에 결합하여 CCR2 발현을 조절함을 규명하였다. 동맥경화 환자의 혈청에서 LZIP이 과 발현되어있음을 관찰하여 LZIP이 동맥경화의 표지자로 역할을 할 수 있음을 제시하였다.본 연구에서 LZIP은 거품세포의 형성뿐만 아니라 동맥경화의 발병 과정에서 중요한 역할을 하는 단백질임을 알 수 있었고, 동맥경화의 새로운 생체 표지자로 사용 될 수 있음을 알 수 있었다. [영문]Although recent studies have shown that several pro-inflammatory proteins can be used as biomarkers for atherosclerosis, the mechanism of atherogenesis is not clear and little information is available regarding proteins that are involved in development of the disease. Atherosclerotic tissue samples were collected from patients in order to identify the proteins involved in atherogenesis. The protein expression profile of atherosclerosis patients was analyzed using two dimensional electrophoresis-based proteomics. Thirty-nine proteins that were differentially expressed in the atherosclerotic aorta compared with the normal aorta were detected. Twenty-seven of these proteins were identified in the MS-FIT database. They are involved in a number of biological processes, including calcium-mediated processes, migration of vascular smooth muscle cells, matrix metalloproteinase activation, and regulation of pro-inflammatory cytokines. Confirmation of differential protein expression was performed by Western blot analysis. Potential applications of these results include identification and characterization of signaling pathways involved in atherogenesis, and further exploration of the role of selected identified proteins in atherosclerosis.Monocyte chemoattractant protein (MCP)-1 and CC chemokine receptor (CCR) 2 play major roles in atherosclerosis development including promoting migration of circulating monocytes to the arterial wall during atherogenesis. The role of the novel transcription factor LZIP in foam cell formation and in expression of MCP-1 and CCR2 during the process of atherosclerosis was investigated. RNase protection analysis showed that LZIP increased mRNA expression of MCP-1, leukotactin-1 (Lkn-1), CCR1, and CCR2 in THP-1 cells. Flow cytometric data showed that surface expressions of both CCR1 and CCR2 were increased by LZIP, which also enhanced the chemotactic activities of MCP-1 and Lkn-1. During the formation of foam cells, LZIP expression was significantly elevated in foam cells and siLZIP inhibited foam cell formation. Results from an electrophoretic mobility shift assay showed that LZIP binds to the C/EBP element in the CCR2 promoter. Western blot data showed that the LZIP level was highly elevated in serum from coronary atherosclerosis patients compared to normal healthy people. These results suggest that LZIP regulates expression of chemokines and chemokine receptors that are involved in development of atherosclerosis and plays an important role in foam cell formation. LZIP is probably a key modulator in atherogenesis and is a putative biomarker for atherosclerosis.-
dc.publisherGraduate School, Yonsei University-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.titleProteomic analysis of differential protein expression in atherosclerosis and regulatory role of human LZIP in development of atherosclerosis-
dc.title.alternative프로테오믹스를 이용한 동맥경화 특이 발현 단백질의 분석 및 LZIP의 동맥경화 발병과정에서의 역할에 관한 연구-
dc.contributor.alternativeNameSung, Ho Joong-
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