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Matrix metalloproteinase-9 (MMP-9) in vivo substrates in left ventricle remodeling process

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Date Issued:
2015
Summary:
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. 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.
Title: Matrix metalloproteinase-9 (MMP-9) in vivo substrates in left ventricle remodeling process.
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Name(s): Tokmina-Roszyk, Dorota
Iyer, R.P.
Lindsey, M.L.
Graduate College
Fields, Gregg B.
Type of Resource: text
Genre: Poster
Date Created: 2015
Date Issued: 2015
Publisher: Florida Atlantic University
Place of Publication: Boca Raton, Fla.
Physical Form: application/pdf
Extent: 1 p.
Language(s): English
Summary: 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. 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.
Identifier: FA00005917 (IID)
Collection: FAU Student Research Digital Collection
Note(s): The Sixth Annual Graduate Research Day was organized by Florida Atlantic University’s Graduate Student Association. Graduate students from FAU Colleges present abstracts of original research and posters in a competition for monetary prizes, awards, and recognition.
Held by: Florida Atlantic University Libraries
Sublocation: Digital Library
Persistent Link to This Record: http://purl.flvc.org/fau/fd/FA00005917
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Host Institution: FAU
Is Part of Series: Florida Atlantic University Digital Library Collections.