Matrix Metalloproteinase-9 Reduces Islet Amyloid Formation by Degrading Islet Amyloid Polypeptide
Matrix Metalloproteinase-9 Reduces Islet Amyloid Formation by Degrading Islet Amyloid Polypeptide
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DOI：
10.1074/jbc.m112.438457
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Hull, Rebecca L.
中科院分区：
文献类型：
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作者：
Aston-Mourney, Kathryn;Zraika, Sakeneh;Hull, Rebecca L.
胰岛淀粉样多肽（IAPP）作为淀粉样蛋白沉积是2型糖尿病胰岛的病理标志，其对β细胞具有毒性。我们以前表明，酶脑啡肽酶减少胰岛淀粉样蛋白沉积，从而减少β细胞凋亡，通过抑制原纤维的形成。另外两种酶，基质金属蛋白酶（MMP）-2和MMP-9，是细胞外明胶酶，能够降解另一种淀粉样蛋白生成肽A β，A β是阿尔茨海默病中淀粉样蛋白沉积的成分。因此，我们研究了MMP-2和MMP-9是否在减少胰岛淀粉样蛋白沉积中起作用。MMP-2和MMP-9 mRNA在小鼠胰岛中存在，但仅检测到MMP-9活性。在人IAPP（hIAPP）转基因小鼠胰岛产生淀粉样蛋白而非转基因胰岛不产生淀粉样蛋白的胰岛培养模型中，广谱MMP抑制剂（GM 6001）和MMP-2/9抑制剂增加淀粉样蛋白形成和所产生的β细胞凋亡。相比之下，特定的MMP-2抑制剂对淀粉样蛋白沉积或β细胞凋亡没有影响。质谱分析表明，MMP-9降解淀粉样hIAPP，但不降解非淀粉样小鼠IAPP。因此，MMP-9构成内源性胰岛蛋白酶，其通过降解hIAPP限制胰岛淀粉样蛋白沉积及其毒性作用。由于胰岛MMP-9 mRNA水平在2型糖尿病受试者中降低，因此胰岛MMP-9活性在人2型糖尿病中也可能降低，从而导致胰岛淀粉样蛋白沉积和β细胞损失增加。增加胰岛MMP-9活性的方法可以减少或预防2型糖尿病中淀粉样蛋白沉积及其毒性作用。
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, A beta, 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.