Forkhead transcription factors (FoxOs) promote apoptosis of insulin-resistant macrophages during cholesterol-induced endoplasmic reticulum stress

Abstract

OBJECTIVE-Endoplasmic reticulum stress increases macrophage apoptosis, contributing to the complications of atherosclerosis. Insulin-resistant macrophages are more susceptible to endoplasmic reticulum stress-associated apoptosis probably contributing to macrophage death and necrotic core formation in atherosclerotic plaques in type 2 diabetes. However, the molecular mechanisms of increased apoptosis in insulin-resistant mac- rophages remain unclear. RESEARCH DESIGN AND METHODS-The studies were performed in insulin-resistant macrophages isolated from insulin receptor knockout or ob/ob mice. Gain- or loss-of-function approaches were used to evaluate the roles of forkhead transcription factors (FoxOs) in endoplasmic reticulum stress-associated macrophage apoptosis. RESULTS-Insulin-resistant macrophages showed attenuated Akt activation and increased nuclear localization of FoxOl during endoplasmic reticulum stress induced by free cholesterol loading. Overexpression of active FoxOl or FoxO3 failed to induce apoptosis in unchallenged macrophages but exacerbated apoptosis in macrophages with an active endoplasmic reticulum stress response. Conversely, macrophages with genetic knockouts of FoxO1, -3, and -4 were resistant to apoptosis in response to endoplasmic reticulum stress. FoxOl was shown by chromatin immunoprecipitation and promoter expression analysis to induce inhibitor of κBΕ gene expression and thereby to attenuate the increase of nuclear p65 and nuclear factor-kB activity during endoplasmic reticulum stress, with proapoptotic and anti-inflammatory consequences. CONCLUSIONS-Decreased Akt and increased FoxO transcription factor activity during the endoplasmic reticulum stress response leads to increased apoptosis of insulin-resistant mac- rophages. FoxOs may have a dual cellular function, resulting in either proapoptotic or anti-inflammatory effects in an endoplas- mic reticulum stress-modulated manner. In the complex plaque milieu, the ultimate effect is likely to be an increase in macro- phage apoptosis, plaque inflammation, and destabilization. © 2008 by the American Diabetes Association.