αmβ 2 Is Antiatherogenic in Female but Not Male Mice

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Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin αMβ 2 (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. αM -/- /ApoE -/- and ApoE -/- mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, αM deficiency accelerated development of atherosclerosis in female but not in male mice. The size of aortic root lesions was 3-4.5-fold larger in female αM -/- /ApoE -/- than in ApoE -/- mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female αM -/- /ApoE -/- mice due to enhanced proliferation. αMβ 2 elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by αM -/- /ApoE -/- macrophages. This difference was attributed to enhanced expression of lipid uptake receptors, CD36 and scavenger receptor A1 (SR-A1), in female mice. Macrophages from female αM -/- /ApoE -/- mice showed dramatically reduced expression of FoxM1 transcription factor and estrogen receptors (ER) a and b. As their antagonists inhibited the effect of 17b-estradiol (E2), E2 decreased CD36, SR-A1, and foam cell formation in ApoE -/- macrophages in an ERa- and ERb-dependent manner. However, female αM -/- /ApoE -/- macrophages failed to respond to E 2 and maintained elevated CD36, SR-A1, and lipid accumulation. FoxM1 inhibition in ApoE -/- macrophages reduced ERs and enhanced CD36 and SR-A1 expression, whereas FoxM1 overexpression in αM -/- /ApoE -/- macrophages reversed their proatherogenic phenotype.We demonstrate a new, surprising atheroprotective role of αMβ 2 in female ApoE -/- mice. αMβ 2 maintains ER expression in macrophages and E 2 -dependent inhibition of foam cell formation.