Granulocyte Colony Stimulating Factor and MT1-MMP Involved in Development of Atherosclerosis in Apolipoprotein E-Deficient Mice

Objectives Genetic deficiency of macrophage colony stimulating factor (M-CSF) in atherosclerosis-prone (apoE-/-) mice markedly reduces formation of atheroma. But Little is known about the potential effects of other colony stimulating factors(CSF),such as granulocyte CSF(G-CSF),on atherosclerosis. This study tested the hypothesis that G-CSF would be involved in development of atherosclerotic plaque. Methods apoE-/-mice fed with a Western-style diet (0.15% cholesterol) were injected subcutaneously with recombinant human G-CSF(10 mg/day) daily for 9 weeks then sacrificed. The matrix metalloproteinase(MMP)2 and MMP9 in serum of mice were measured by Gelatin Zymography analysis and c-kit and membrane type1-MMP(MT1-MMP) antigens were detected using fluorescence activated cell sorting (FACS). Meanwhile,complete blood counts (CBC) and serum cholesterol,relative fractions of VLDL,LDL,and HDL were evaluated by spectrophotometric techniques and high performance liquid chromatography (HPLC) respectively. Atherosclerotic Lesions of the aorta were also analyzed by histological methods. Results G-CSF treatment resulted in increased proportions of circulating monocytes (6.9± 2.2% vs. 3.8± 0.3%; P<0.05),and decreased serum levels of total cholesterol(1225± 594 vs. 1991± 1009; P<0.005) compared to control mice. A greater proportion of bone marrow cells from G-CSF treated mice expressed MT1-MMP (14.5± 5.5% vs. 6.2± 5.0%,P<0.05) compared to bone marrow cells from vehicle treated mice. G-CSF treatment was also associated with smaller atheromatous plaque,and decreased oil red O staining. Conclusions G-CSF lowers serum cholesterol,increases circulating monocytes,increases bone marrow cell expression of MT1-MMP,inhibits plaque development,and decreases lipid and macrophage infiltration into developing plaque.