Matrix Metalloproteinase-9 Protects Islets from Amyloid-induced Toxicity.
J Biol Chem
; 290(51): 30475-85, 2015 Dec 18.
Article
em En
| MEDLINE
| ID: mdl-26483547
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 increased ß-cell apoptosis and reduced ß-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 ß-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 ß cells. Mixtures of these fragments with full-length hIAPP did not modulate the kinetics of fibril formation by full-length 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 amyloid-prone islets reduced amyloid deposition and ß-cell apoptosis. These findings suggest that increasing islet MMP-9 activity might be a strategy to limit ß-cell loss in type 2 diabetes.
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MEDLINE
Assunto principal:
Peptídeos
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Apoptose
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Metaloproteinase 9 da Matriz
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Diabetes Mellitus Tipo 2
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Células Secretoras de Insulina
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Polipeptídeo Amiloide das Ilhotas Pancreáticas
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article