Insulin-induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes/macrophages
Gorka San José (a), Julen Bidegain (a), Pablo A. Robador (a), Javier Díez (a, b), Ana Fortuño (a) and Guillermo Zalba (a)
(a) Division of Cardiovascular Sciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
(b) Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain
Magazine: Free Radical Biology and Medicine
Date: Apr 15, 2009Cardiology
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.
CITATION Free Radic Biol Med. 2009 Apr 15;46(8):1058-67
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