Matrix metalloproteinase-9 protects islets from amyloidinduced toxicity

Daniel T. Meier, Ling Hsien Tu, Sakeneh Zraika, Meghan F. Hogan, Andrew T. Templin, Rebecca L. Hull, Daniel P. Raleigh, Steven E. Kahn

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Abstract

Deposition of human islet amyloid polypeptide (hIAPP, also known as amylin) as islet amyloid is a characteristic feature of the pancreas in type 2 diabetes, contributing to increasedβ-cell apoptosis and reduced β-cell mass. Matrix metalloproteinase-9 (MMP-9) is active in islets and cleaves hIAPP. We investigated whether hIAPP fragments arising from MMP-9 cleavage retain the potential to aggregate and cause toxicity, and whether overexpressing MMP-9 in amyloid-prone islets reduces amyloid burden and the resulting β-cell toxicity. Synthetic hIAPP was incubated with MMP-9 and the major hIAPP fragments observed by MS comprised residues 1-15, 1-25, 16-37, 16-25, and 26-37. The fragments 1-15, 1-25, and 26-37 did not form amyloid fibrils in vitro and they were not cytotoxic when incubated with β cells. Mixtures of these fragments with full-length hIAPP did not modulate the kinetics of fibril formation by fulllength hIAPP. In contrast, the 16-37 fragment formed fibrils more rapidly than full-length hIAPP but was less cytotoxic. Co-incubation of MMP-9 and fragment 16-37 ablated amyloidogenicity, suggesting that MMP-9 cleaves hIAPP 16-37 into non-amyloidogenic fragments. Consistent with MMP-9 cleavage resulting in largely non-amyloidogenic degradation products, adenoviral overexpression of MMP-9 in amyloidprone islets reduced amyloid deposition and β-cell apoptosis. These findings suggest that increasing islet MMP-9 activity might be a strategy to limit β-cell loss in type 2 diabetes.

Original languageEnglish
Pages (from-to)30475-30485
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number51
DOIs
Publication statusPublished - 2015 Dec 18

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Meier, D. T., Tu, L. H., Zraika, S., Hogan, M. F., Templin, A. T., Hull, R. L., Raleigh, D. P., & Kahn, S. E. (2015). Matrix metalloproteinase-9 protects islets from amyloidinduced toxicity. Journal of Biological Chemistry, 290(51), 30475-30485. https://doi.org/10.1074/jbc.M115.676692