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Matrix Metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide

Aston-Mourney, Kathryn, Zraika, Sakeneh, Udayasankar, Jayalakshmi, Subramanian, Shoba L., Green, Pattie S., Kahn, Steve E. and Hull, Rebecca L. 2013, Matrix Metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide, The journal of biological chemistry, vol. 288, no. 5, pp. 3553-3559, doi: 10.1074/jbc.M112.438457.

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Title Matrix Metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide
Author(s) Aston-Mourney, KathrynORCID iD for Aston-Mourney, Kathryn orcid.org/0000-0003-1412-6715
Zraika, Sakeneh
Udayasankar, Jayalakshmi
Subramanian, Shoba L.
Green, Pattie S.
Kahn, Steve E.
Hull, Rebecca L.
Journal name The journal of biological chemistry
Volume number 288
Issue number 5
Start page 3553
End page 3559
Total pages 7
Publisher American Society for Biochemistry and Molecular Biology
Place of publication Bethesda, Maryland
Publication date 2013-02
ISSN 0021-9258
1083-351X
Keyword(s) alzheimer disease
amyloid deposition
amyloid deposits
amyloid formation
amyloidogenic peptides
Summary Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but nontransgenic islets do not, a broad spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.
Language eng
DOI 10.1074/jbc.M112.438457
Field of Research 110107 Metabolic Medicine
Socio Economic Objective 920104 Diabetes
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2013, American Society for Biochemistry and Molecular Biology
Persistent URL http://hdl.handle.net/10536/DRO/DU:30059487

Document type: Journal Article
Collection: School of Medicine
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