αmβ \u3csub\u3e2\u3c/sub\u3e Is Antiatherogenic in Female but Not Male Mice

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

Molecular cloning of hamster lipid transfer inhibitor protein (apolipoprotein F) and regulation of its expression by hyperlipidemia*

Lipid transfer inhibitor protein (LTIP) is a regulator of cholesteryl ester transfer protein (CETP) function. Factors affecting plasma LTIP levels are poorly understood. In humans, plasma LTIP is elevated in hypercholesterolemia. To define possible mechanisms by which hyperlipidemia modifies LTIP, we investigated the effects of hypercholesterolemic diets on plasma LTIP and mRNA levels in experimental animals. The hamster, which naturally expresses CETP, was shown to express LTIP. Hamster LTIP mRNA, exclusively detected in the liver, defined a predicted LTIP protein that is 69% homologous to human, with an isoelectric point of 4.15 and Mr = ∼16.4 kDa. Hyperlipidemia induced by feeding hydrogenated coconut oil, cholesterol, or both lipids increased plasma LTIP mass up to 2.5-fold, with LTIP mass correlating strongly with plasma cholesterol levels. CETP mass was similarly affected by these diets. In contrast, these diets reduced LTIP hepatic mRNA levels by >50%, whereas CETP mRNA was increased. Similar results for both CETP and LTIP were also observed in cholesterol-fed rabbits. In conclusion, we report in hamster and rabbit that dietary lipids regulate LTIP. Diet-induced hypercholesterolemia markedly increased plasma LTIP mass while concomitantly depressing LTIP gene expression. CETP and LTIP have distinct responses to dietary lipids