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Matrix metalloproteinase-9 (MMP-9) in vivo substrates in left ventricle remodeling process
Title
Matrix metalloproteinase-9 (MMP-9) in vivo substrates in left ventricle remodeling process.
Creator
Tokmina-Roszyk, Dorota, Iyer, R.P., Lindsey, M.L., Graduate College, Fields, Gregg B.
Abstract/Description
Matrix metalloproteinase-9 MMP-9 is involved in the early stages of wound healing, including the inflammatory reaction that follows myocardial infarction and neovascularization. However, its overexpression in the infarct zone leads to deleterious effects. Understanding MMP-9 function and modulation of its activity provides an opportunity to prevent excessive remodeling of the left ventricle. To assess the role of MMP-9 in remodeling process we employed a broad search of in vivo substrates....
Show moreMatrix metalloproteinase-9 MMP-9 is involved in the early stages of wound healing, including the inflammatory reaction that follows myocardial infarction and neovascularization. However, its overexpression in the infarct zone leads to deleterious effects. Understanding MMP-9 function and modulation of its activity provides an opportunity to prevent excessive remodeling of the left ventricle. To assess the role of MMP-9 in remodeling process we employed a broad search of in vivo substrates. Based on comparative analysis of MMP-9 null and wild type mice, several peptides mimicking putative substrates were synthesized. The cleavage sites in the substrates were identified using high performance liquid chromatography and mass spectrometry. Peptide mapping studies revealed MMP-9 cleavage sites in several proteins, potential biomarkers of excessive remodeling. Specifically, osteopontin, thrombospondin and C-terminal telopeptide regions of type I collagen were susceptible to proteolysis by MMP-9. The best target for MMP-9 was fibronectin, which has multiple cleavage sites in its sequence. In addition to in vivo substrate screening, a selective triple-helical peptide inhibitor MMP- 9i has been designed, synthesized, and utilized as an MMP-9 probe. The sequence of inhibitor was derived from the known MMP-9 substrate type V collagen. In the MMP-9i construct, the G~V scissile bond has been replaced with phosphinate moiety that mimics the transition state of hydrolysis but cannot be cleaved. MMP-9i's effect on MMP-9 activity in serum was tested in a mouse model. The administration of MMP-9i resulted in 30 loss of MMP-9 activity suggesting that MMP-9i can be utilized to regulate activity of MMP-9 in vivo.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00005917
Format
Document (PDF)
Inhibition of matrix metalloproteinase-9 reduces clinical severity in a murine model of Multiple Sclerosis
Title
Inhibition of matrix metalloproteinase-9 reduces clinical severity in a murine model of Multiple Sclerosis.
Creator
Onwuha-Ekpete, Lillian C., Tokmina-Roszyk, Dorota, Fields, Gregg B., Graduate College
Abstract/Description
Matrix metalloproteinases MMPs are a family of proteolytic enzymes that mediate the degradation of various components of the extracellular matrix. Their functions are essential for normal physiological processes such as wound healing, but their dysregulation is associated with various pathologies including autoimmune diseases such as Multiple Sclerosis MS. Experimental Autoimmune Encephalomyelitis EAE is a well-established murine model of MS that is mediated by CD4 T-cells. These cells...
Show moreMatrix metalloproteinases MMPs are a family of proteolytic enzymes that mediate the degradation of various components of the extracellular matrix. Their functions are essential for normal physiological processes such as wound healing, but their dysregulation is associated with various pathologies including autoimmune diseases such as Multiple Sclerosis MS. Experimental Autoimmune Encephalomyelitis EAE is a well-established murine model of MS that is mediated by CD4 T-cells. These cells penetrate the blood-brain-barrier BBB, recruit other immune cells, initiate destruction of the myelin sheath, and cause axonal loss. MMP-9 is a hallmark enzyme in progression of MS that is required for penetration of the BBB and generation of autoantigens in EAE. In addition, recent studies have demonstrated that MMP-9 contributes to normal intracellular function of various cell types including antigen activated T-cells; however, the intracellular role of MMP-9 in immune cell activation during EAE pathogenesis is not known. In this study, we used a highly selective MMP-9 triple-helical peptide inhibitor THPI that is a phosphinate transition state analog to examine antigen specific T-cell responses. We found that selective inhibition of MMP-9 can mitigate pathogenic T-cell activity and cellular trafficking as well as the clinical severity of EAE, suggesting that selective MMP-9 inhibition in MS can be a potent therapeutic option.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00005904
Format
Document (PDF)
THE ROLE OF MATRIX METALLOPROTEINASE-28 IN HEALTH AND DISEASE
Title
THE ROLE OF MATRIX METALLOPROTEINASE-28 IN HEALTH AND DISEASE.
Creator
Tokmina-Roszyk, Dorota, Fields, Gregg B., Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
Matrix Metalloproteinase-28 (MMP-28) is the newest and least characterized member of MMP family. To date several potential substrate candidates for MMP-28 have been proposed but no in vivo substrates for this enzyme were confirmed. In the central nervous system (CNS) MMP-28 is believed to be important factor during myelination of the developing nervous system as well as during remyelination that follows neuronal injury. On the other hand, MMP-28 has been found in actively demyelinating...
Show moreMatrix Metalloproteinase-28 (MMP-28) is the newest and least characterized member of MMP family. To date several potential substrate candidates for MMP-28 have been proposed but no in vivo substrates for this enzyme were confirmed. In the central nervous system (CNS) MMP-28 is believed to be important factor during myelination of the developing nervous system as well as during remyelination that follows neuronal injury. On the other hand, MMP-28 has been found in actively demyelinating lesions in both experimental autoimmune encephalopathy (EAE) and multiple sclerosis patients suggesting its possible role in pathological events associated with autoimmune neurodegenerative processes. In addition, MMP-28 has been linked to modulation of immune response and activation of macrophages which presents another role of this enzyme in autoimmune pathologies. In the study described herein, MMP-28 has been shown to affect myelin composition and appearance, mitochondrial protein content, and vesicular transport proteins. Moreover, the decrease in myelin basic protein quantity observed in healthy MMP-28KO animals affected the myelin staining intensity in various brain regions including corpus callous. Cellular energetic studies did not reveal differences in mitochondrial function in MMP-28KO animals and no difference in reactive oxygen species was observed. In the EAE model, MMP-28 deletion increased the occurrence of atypical form of EAE characterized by increased inflammation of arbor vitae of the brain. In addition, MMP-28 deletion decreased the inflammatory infiltrates present in brains obtained from EAE animals. Lastly, MMP-28 has been shown to affect cellular energetics and activation of bone marrow derived macrophages during the initial stages and after 24 h activation. In addition, MMP-28 deletion increased proinflammatory cytokines and receptors CD86 and iNOS found in M1 polarized macrophages.
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Date Issued
2020
PURL
http://purl.flvc.org/fau/fd/FA00013601
Subject Headings
Matrix Metalloproteinases, Multiple sclerosis, Neurodegenerative disease
Format
Document (PDF)