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Cysteine-rich angiogenic protein 61-induced ectopic mineralization is mediated by activation of matrix metalloproteinases in vascular smooth muscle cells
혈관 평활근 세포의 CYR61 단백에 의해 매개되는 이소성 무기화 작용은 기질금속단백분해효소의 활성화에 의해 매개된다

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Authors
김치훈
Advisor
김효수
Major
융합과학기술대학원 분자의학 및 바이오제약학과
Issue Date
2016-02
Publisher
서울대학교 융합과학기술대학원
Keywords
Cysteine-rich angiogenic protein 61Matrix metalloproteinaseMineralizationVascular calcification
Description
학위논문 (석사)-- 서울대학교 융합과학기술대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과 분자의학 및 바이오제약학 전공, 2016. 2. 김효수.
Abstract
Background: Cysteine-rich angiogenic protein 61 (CYR61) was reported to be induced by angiotensin II in vascular smooth muscle cells (VSMCs), and it is a key regulatory molecule in ectopic mineralization of osteogenic transdifferentiated VSMCs. But, exact molecular mechanism of CYR61-induced mineralization is unclear, so we explored downstream effector molecule of CYR61.

Methods and Results: VSMCs harvested from thoracic aortas of male C57BL6 mice were transfected with adenoviral vector containing Cyr61 (Ad-CYR61), and then microarray analysis was performed to evaluate the effects of CYR61 on VSMC mineralization. Several matrix metalloproteinases such as MMP-13, MMP-3 and MMP-10 were immediately increased by 7.9, 6.5, and 2.0-folds after 24 hours of transfection. However, tissue inhibitors of metalloproteinases such as TIMP-3 and TIMP-2 were reduced by 52% and 71%, respectively (all p<0.05). Real-time PCR confirmed MMP-13 gene induction by 33±13 folds compared to control adenovirus-transfected VSMCs (p<0.05). Although mRNA expression of MMP-9 was not found to be increased, gelatin zymography showed an augmented enzymatic activity of MMP-9 by Ad-CYR61 transfection, which was significantly decreased by siRNA for MMP-13. In the light microscopic analysis with Von Kossa staining or electron microscopic examinations, dominant negative adenoviral vector for c-Jun and broad spectrum MMP inhibitor doxycycline can minimize or attenuate CYR61-medated ECM disruption or ectopic mineralization.

Conclusion: These findings demonstrate that CYR61-mediated MMP activation is important to induce vascular calcification in the milieu of systemic inflammation. Therapies targeting to CYR61 or MMPs may modulate vascular calcification and could have clinical implications.
Language
English
URI
https://hdl.handle.net/10371/133391
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Theses (Master's Degree_분자의학 및 바이오제약학과)
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