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Studies on the regulation of the activity potential of Matrix Metalloproteinase 2
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- Author / Creator
- Sarker, Hassan Z
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Matrix metalloproteinase 2 (MMP2), also known as gelatinase A or 72 kDa type IV collagenase, is a member of a family of 25 different Zn2+-dependent endopeptidases that cleave a broad range of proteins including extracellular matrix proteins (such as collagens, laminin, fibrillin and aggrecan), cell surface receptors (e.g., the insulin receptor), growth factors as well as cytokines and chemokines (such as monocyte chemoattractant protein-3). Excessive and deficient MMP2 activity can contribute to pathogenesis of osteoarthritis, cancer, and cardiovascular diseases. Our understanding of the cellular biology of MMPs in the vascular endothelium, vascular smooth muscle, and myocardium has undergone major advances in recent decades. However, the roles of MMPs in the circulatory system have not been clarified. The molecular interactome of MMPs in the blood has not been elucidated. It is unclear whether all MMPs circulate free or bound to endogenous inhibitors or to other proteins found in the blood whose large abundance makes them putative interactors that may influence the activity potential of MMPs in the blood. Clarifying the transport and regulation of MMP2 in the blood circulation was one of the objectives of this research. This research extends the phenotypic characterization of MMP2 deficiency to include circulating levels of cytokines and chemokines, soluble cytokine receptors, angiogenesis factors, bone development factors, apolipoproteins and hormones. Investigations into the interactome of MMP2 in the plasma led to the identification of fibrinogen – an acute phase reactant – as a natural inhibitor of MMP2 exhibiting a mixed-type (combination of competitive and non-competitive) inhibition mechanism. Furthermore, we found that apolipoprotein A1 – the major protein component of high-density lipoprotein (HDL) - allosterically increases the proteolytic activity of MMP2. This finding revealed MMP2 to be an allosteric enzyme. Together, the findings presented in this thesis indicate that a network of blood-borne proteins, including fibrinogen and ApoA1/HDL, may regulate the activity potential of MMP2 in the circulation. We postulate a novel hypothesis: blood-borne proteins, including fibrinogen and ApoA1/HDL, bind MMP2 effectively acting as “transporter and regulator of the activity potential (TRAP)” complexes of MMP2 and may cause MMP2 activity to increase, decrease or remain unchanged—without immediate biological effects—while simultaneously enabling secreted MMP2 in the blood to reach distal target organs and participate in inter-organ communication.
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- Subjects / Keywords
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- Graduation date
- Spring 2024
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.