role of matrix metalloproteinase-2 in therosclerosis and abdominal aortic aneurysms in ...

167 Pages·2016·2.91 MB·English

by  Jing Huang

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University of Kentucky Doctoral Dissertations Graduate School
2005
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University of Kentucky, [email protected]
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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
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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
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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