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UUnniivveerrssiittyy ooff KKeennttuucckkyy UUKKnnoowwlleeddggee University of Kentucky Doctoral Dissertations Graduate School 2005 RROOLLEE OOFF MMAATTRRIIXX MMEETTAALLLLOOPPRROOTTEEIINNAASSEE--22 IINN TTHHEERROOSSCCLLEERROOSSIISS AANNDD AABBDDOOMMIINNAALL AAOORRTTIICC AANNEEUURRYYSSMMSS IINN AAPPOOLLIIPPOOPPRROOTTEEIINN EE DDEEFFIICCIIEENNTT MMIICCEE Jing Huang University of Kentucky, [email protected] RRiigghhtt cclliicckk ttoo ooppeenn aa ffeeeeddbbaacckk ffoorrmm iinn aa nneeww ttaabb ttoo lleett uuss kknnooww hhooww tthhiiss ddooccuummeenntt bbeenneefifittss yyoouu.. RReeccoommmmeennddeedd CCiittaattiioonn Huang, Jing, "ROLE OF MATRIX METALLOPROTEINASE-2 IN THEROSCLEROSIS AND ABDOMINAL AORTIC ANEURYSMS IN APOLIPOPROTEIN E DEFICIENT MICE" (2005). University of Kentucky Doctoral Dissertations. 473. https://uknowledge.uky.edu/gradschool_diss/473 This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION Jing Huang The Graduate School University of Kentucky 2005 ROLE OF MATRIX METALLOPROTEINASE-2 IN ATHEROSCLEROSIS AND ABDOMINAL AORTIC ANEURYSMS IN APOLIPOPROTEIN E DEFICIENT MICE ABSTRACT OF DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Jing Huang Lexington, Kentucky Director: Dr. Alan Daugherty, Professor of Medicine and Physiology Lexington, Kentucky 2005 Copyright © Jing Huang 2005 ABSTRACT OF DISSERTATION ROLE OF MATRIX METALLOPROTEINASE-2 IN ATHEROSCLEROSIS AND ABDOMINAL AORTIC ANEURYSMS IN APOLIPOPROTEIN E DEFICIENT MICE Matrix metalloproteinase-2 (MMP-2, gelatinase A, type IV collagenase) is a member of a family of zinc-dependent metalloendopeptidases that functions in the degradation of elastin, collagens, and other components of extracellular matrix (ECM). Both secretion and activation of MMP-2 are elevated in human atherosclerotic lesions and abdominal aortic aneurysms (AAA). In this dissertation project, we sought to test the hypothesis that MMP-2 plays a critical role in both atherosclerosis and AAA. We also sought to determine the detailed mechanism. We first examined the atherosclerosis and AngII-induced AAAs development in MMP-2-/- x apolipoprotein (apoE)-/- mice in vivo. It was surprising that MMP-2 deficiency did not reduce the incidence of AngII-induced AAAs or the size of atherosclerosis in apoE-/- mice. However, the cellular and ECM content of atherosclerotic plaques were modified in MMP-2-/- x apoE-/- mice as compared to MMP-2+/+ x apoE-/- control mice. To explain the apparent paradox between this result and the hypothesis, we investigated the morphological characteristics of the aortic wall of MMP-2-/- mice. We detected an enhanced MMP-9 level in the aortic wall of MMP-2-/- x apoE-/- mice compared with MMP-2+/+ x apoE-/- mice. Interestingly, we also observed more branching of the elastin fibers in aortic wall of MMP-2-/- mice as compared with aorta of wild type mice. We also examined the behavior of macrophages from MMP-2-/- mice. Reduced adhesion, migration, and expression of integrin beta 3 were detected in MMP-2 deficient macrophages compared with wild type macrophages. Lastly, we examined whether MMP-2 deficiency in bone marrow-derived cells may influence AAAs and atherosclerosis using bone marrow transplantation technique. There was a significant reduction of both atherosclerosis development and AAAs formation in mice that were reconstituted MMP-2-/- bone marrow cells. In conclusion, the findings in this dissertation suggest that MMP-2 might play an important role in atherosclerosis and aneurysm through influencing inflammatory cell infiltration. KEYWORDS: matrix metalloproteinase-2, atherosclerosis, abdominal aortic aneurysm, integrin, macrophage Jing Huang ROLE OF MATRIX METALLOPROTEINASE-2 IN ATHEROSCLEROSIS AND ABDOMINAL AORTIC ANEURYSMS IN APOLIPOPROTEIN E DEFICIENT MICE By Jing Huang Director of Dissertation Director of Graduate Studies Date RULES FOR THE USE OF DISSERTATIONS Unpublished dissertations submitted for the Doctor’s degree and deposited in the University of Kentucky Library are as a rule open for inspection, but are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but quotations or summaries of parts may be published only with the permission of the author, and with the usual scholarly acknowledgements. Extensive copying or publication of the dissertation in whole or in part requires also the consent of the Dean of the Graduate School of the University of Kentucky. A library that borrows this dissertation for use by its patrons is expected to secure the signature of each user. NAME DATE DISSERTATION Jing Huang The Graduate School University of Kentucky 2005 ROLE OF MATRIX METALLOPROTEINASE-2 IN ATHEROSCLEROSIS AND ABDOMINAL AORTIC ANEURYSMS IN APOLIPOPROTEIN E DEFICIENT MICE DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Jing Huang Lexington, Kentucky Director: Dr. Alan Daugherty, Professor of Medicine and Physiology Lexington, Kentucky 2005 Copyright © Jing Huang 2005
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