NADPH氧化酶
基质金属蛋白酶
化学
细胞生物学
金属蛋白酶
基质金属蛋白酶9
巨噬细胞
胰岛素
酶
内分泌学
生物化学
医学
生物
体外
作者
Gorka San José,Julen Bidegain,Pablo A. Robador,Javier Dı́ez,Ana Fortuño,Guillermo Zalba
标识
DOI:10.1016/j.freeradbiomed.2009.01.009
摘要
Insulin stimulates superoxide (O(2)(-)) production in monocytes and macrophages. However, the mechanisms through which insulin induces O(2)(-) production are not completely understood. In this study, we (a) characterized the enzyme and the pathways involved in insulin-stimulated O(2)(-) production in human monocytes and murine macrophages, and (b) analyzed the consequences of insulin-stimulated O(2)(-) production on the cellular phenotype in these cells. We showed that insulin stimulated O(2)(-) production, and promoted p47(phox) translocation to the plasma membrane. Insulin-induced O(2)(-) production and p47(phox) translocation were prevented in the presence of specific inhibitors of PI3K and PKC. Insulin-mediated NADPH oxidase activation stimulated MMP-9 activation in monocytes and cell proliferation in macrophages. The effect of insulin on these phenotypic responses was mediated through NFkappaB, p38MAPK, and ERK 1/2 activation. Small-interfering RNA-specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression, decreased insulin-induced O(2)(-) production, inhibited the turn on of NFkappaB, p38MAPK, and ERK 1/2, and reduced cell proliferation in macrophages. These findings suggest a pivotal role for NADPH oxidase in insulin-induced proliferation and proteolytic activation in monocytes and macrophages, respectively, and identify a pathway that may play a pathological role in hyperinsulinemic states.
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