Macrophage-derived foam cells express apolipoprotein E (apoE) abundantly in atherosclerotic lesions. To examine the physiologic role of apoE secretion by the macrophage in atherogenesis, bone marrow transplantation was used to reconstitute C57BL/6 mice with macrophages that were either null or wild type for the apoE gene. After 13 weeks on an atherogenic diet, C57BL/6 mice reconstituted with apoE null marrow developed 10-fold more atherosclerosis than controls in the absence of significant differences in serum cholesterol levels or lipoprotein profiles. ApoE expression was absent in the macrophage-derived foam cells of C57BL/6 mice reconstituted with apoE null marrow. Thus, lack of apoE expression by the macrophage promotes foam cell formation.
Expression of lipoprotein lipase (LPL) by the macrophage has been proposed to promote foam cell formation and atherosclerosis, primarily on the basis of in vitro studies. LPL-deficient mice might provide a model for testing the role of LPL secretion by the macrophage in an in vivo system. Unfortunately, homozygous deficiency of LPL in the mouse is lethal shortly after birth. Because the fetal liver is the major site of hematopoiesis in the developing fetus, transplantation of C57BL/6 mice with LPL -/-fetal liver cells (FLCs) was used to investigate the physiologic role of macrophage LPL expression in vivo. Thirty-four female C57BL/6 mice were lethally irradiated and reconstituted with FLCs from day 14 LPL +/+ , LPL +/-, and LPL -/-donors. No significant differences were detected in plasma levels of post-heparin LPL activity or in serum cholesterol or triglyceride levels between the 3 groups on either a chow diet or an atherogenic diet. After 19 weeks on the atherogenic diet, aortae were collected for quantitative analysis of the extent of aortic atherosclerosis. LPL expression was detected by immunocytochemistry and in situ hybridization in macrophages of aortic atherosclerotic lesions of LPL +/+ →C57BL/6 and LPL +/-→C57BL/6 mice, but not in LPL -/-→C57BL/6 mice, whereas myocardial cells expressed LPL in all groups. The mean aortic lesion area was reduced by 55% in LPL -/-→C57BL/6 mice compared with LPL +/+ →C57BL/6 mice and by 45% compared with LPL +/-→C57BL/6 mice, respectively. These data demonstrate in vivo that LPL expression by macrophages in the artery wall promotes foam cell formation and atherosclerosis.
The role of specific stromal-derived matrix metalloproteinases (MMPs) was analyzed in experimental metastasis assays in wild-type and either MMP-9, MMP-7, or MMP-2 null mice. MMP-9 null mice showed an 81% reduction in Lewis lung carcinoma tumor number, whereas MMP-7 null mice showed a 42% increase in tumor number, and there was no difference in tumor number in MMP-2 null mice compared with wild-type controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP-9 null mice were able to establish tumors in the lung compared with control mice, although the size of the tumors was not different. The effect of MMP-9 on lung tumor colonization was dependent on the expression of MMP-9 from bone marrow-derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP-9, bioluminescence imaging from luciferase-expressing human lung cancer-derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP-9 null mice as early as 19 hours after injection compared with control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP-9 null mice showed a 4-fold increase in the percent of tumor cells undergoing apoptosis compared with control mice. We conclude that MMP-9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of MMP inhibitors in clinical trials in patients with late-stage lung cancer. (Cancer Res 2006; 66(1): 259-66)
Matrix metalloproteinases (MMP) are a family of enzymes with a myriad of functions. Lately, we have come to realize that broad-spectrum inhibition of these enzymes, as was tried unsuccessfully in multiple phase III trials in cancer patients, is likely unwise given the protumorigenic and antitumorigenic functions of various family members. Here, we used the multistage mammary tumor model MMTV-PyVT to investigate roles for either MMP7 or MMP9 in tumor progression. We found no effect of genetic ablation of MMP7 or MMP9 on the multifocal tumors that developed in the mammary glands. Lack of MMP7 also had no effect on the development of lung metastases, suggesting that MMP7 is irrelevant in this model. In contrast, MMP9 deficiency was associated with an 80% decrease in lung tumor burden. The predominant cellular source of MMP9 was myeloid cells, with neutrophils being the largest contributor in tumor-bearing lungs. Experimental metastasis assays corroborated the role of host-derived MMP9 in lung metastasis and also facilitated determination of a time frame most relevant for the MMP9-mediated effect. The lung tumors from MMP9-deficient mice showed decreased angiogenesis. Surprisingly, the antimetastatic outcome of MMP9 ablation seemed to be dependent on strain. Only mice that had genetic background derived from C57BL/6 showed reduced metastasis, whereas mice fully of the FVB/N background showed no significant effect. These strain-specific responses were also observed in a study using a highly selective pharmacologic inhibitor of MMP9 and thus suggest that responses to MMP inhibition are controlled by genetic differences. [Cancer Res 2008;68(15):6251-9]
Abstract-The absence of the scavenger receptor A (SR-A)-I/II has produced variable effects on atherosclerosis in different murine models. Therefore, we examined whether SR-AI/II deficiency affected atherogenesis in C57BL/6 mice, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, and whether the deletion of macrophage SR-AI/II expression would modulate lesion growth in C57BL/6 mice and LDL receptor (LDLR) Ϫ/Ϫ mice. SR-AI/II-deficient (SR-AI/IIϪ/Ϫ ) female and male mice on the C57BL/6 background were challenged with a butterfat diet for 30 weeks. No differences were detected in plasma lipids between SR-AI/II Ϫ/Ϫ and SR-AI/II ϩ/ϩ mice, whereas both female and male SR-AI/II Ϫ/Ϫ mice had a tremendous reduction (81% to 86%) in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ mice. Next, to analyze the effect of macrophage-specific SR-AI/II deficiency in atherogenesis, female C57BL/6 mice were lethally irradiated, transplanted with SR-AI/II Ϫ/Ϫ or SR-AI/II ϩ/ϩ fetal liver cells, and challenged with the butterfat diet for 16 weeks. In a separate experiment, male LDLR Ϫ/Ϫ mice were reconstituted with SR-AI/II Ϫ/Ϫ or SR-AI/II ϩ/ϩ fetal liver cells and challenged with a Western diet for 10 weeks. No significant differences in plasma lipids and lipoprotein profiles were noted between the control and experimental groups in either experiment. SR-AI/II Ϫ/Ϫ 3 C57BL/6 mice, however, had a 60% reduction in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ 3 C57BL/6 mice. A similar level of reduction (60%) in lesion area was noted in the proximal aorta and the entire aorta en face of SR-AI/II 4,5 that are generated through alternative splicing of a single gene. 6 The uptake of modified-LDL cholesterol by SR-AI/II has been proposed to play a key role in the pathogenesis of atherosclerosis by promoting lipid accumulation and foam cell formation by the macrophage. 7 The SR-AI/II is expressed predominantly by macrophages 8,9 and is widely expressed by macrophages and foam cells of atherosclerotic lesions. 10 -12 However, smooth muscle cells and endothelial cells may also express the SR-AI/II, 13,14 particularly in the presence of oxidative stress and certain growth factors in vitro 15 and in vivo. 16 The relative contributions of SR-AI/II expression by macrophages, endothelial cells, and smooth muscle cells to atherosclerotic lesion formation in vivo remain uncertain. See page 2506The development of mice with targeted disruption of the SR-AI/II gene provided an important model in which to examine the role of the SR-AI/II in atherosclerosis in vivo, 17 yet the results of these studies have been conflicting. [17][18][19] The absence of SR-AI/II in apoE-deficient (apoE Ϫ/Ϫ ) mice induced a 58% reduction in lesion size compared with control apoE Ϫ/Ϫ mice. 17 In contrast, mice deficient for both the SR-AI/II (SR-AI/II Ϫ/Ϫ ) and the LDL receptor (LDLR Ϫ/Ϫ ) had 28% and 23% reductions in aortic lesion area after 4 and 12 weeks, respectively, of a high-fat diet containing 1.25%...
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