| First Author | Aston-Mourney K | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 5 | Pages | 3553-9 |
| PubMed ID | 23229548 | Mgi Jnum | J:335478 |
| Mgi Id | MGI:6868274 | Doi | 10.1074/jbc.M112.438457 |
| Citation | Aston-Mourney K, et al. (2013) Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide. J Biol Chem 288(5):3553-9 |
| abstractText | Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to beta-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces beta-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, Abeta, 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 beta-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or beta-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 beta-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes. |
