Abstract-Mice expressing human apolipoprotein A-IV (apoA-IV) mainly in the intestine were obtained in an apolipoprotein E-deficient (apoE 0 ) background (apoA-IV/E 0 mice). Quantification of aortic lesions and plasma lipid determination showed that compared with their control apoE 0 counterparts, the apoA-IV/E 0 mice are protected against atherosclerosis without an increase in HDL cholesterol. Because oxidized lipoproteins play an important role in atherogenesis, we tested whether the protection observed in these animals is accompanied by an in vivo reduction of the oxidation parameters. The lag time in the formation of conjugated dienes during copper-mediated oxidation, the aggregation state of LDL, and the presence of anti-oxidized LDL antibodies were measured. The presence of oxidized proteins in tissues and the presence of oxidation-specific epitopes in heart sections of atherosclerotic lesions were also analyzed. Except for lag time, the results showed that the oxidation parameters were reduced in the apoA-IV/E 0 mice compared with the apoE 0 mice. This suggests that human apoA-IV acts in vivo as an antioxidant. In addition, human apoA-IV accumulation was detected in the atherosclerotic lesions of apoA-IV/E 0 mice, suggesting that apoA-IV may inhibit oxidative damage to local tissues, thus decreasing the progression of atherosclerosis. (Arterioscler Thromb Vasc

Atherosclerosis has many features of a chronic inflammatory disease. To evaluate the role of lipopolysaccharide (LPS), mimicking a systemic infection, we administered the endotoxin to apolipoprotein E (apoE)-deficient mice. LPS injections increase the atherosclerotic lesion size and the titer of plasma autoantibodies directed against oxidized low-density lipoprotein. We found that Th1 and Th2 T cells help the activation of B cells in the autoimmune response. The number of interleukin-4 producing natural killer T cells is highly increased in peripheral blood, liver, spleen and thymus cells, as well as in the atherosclerotic plaque of the LPS-treated mice. Finally, an important adventitial infiltrate of activated lymphocytes, sign of an advanced atherosclerosis, is observed only in the LPS-treated mice. Our results demonstrate that LPS administration aggravates atherosclerosis in apoE-deficient mice. LPS-injected apoEdeficient mice appear to be an excellent animal model to analyze the implementation of new therapeutic approaches in the treatment of atherosclerosis by manipulating immunological effectors. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Objective— Expression of human apolipoprotein (h-apo) A-IV in apoE-deficient (apoE 0 ) mice (h-apoA-IV/E 0 ) reduces susceptibility to atherosclerosis. Chronic infection mimicked by exposure to lipopolysaccharide (LPS) increases the size of atherosclerosis lesions in apoE 0 mice. Thus, we used h-apoA-IV/E 0 mice to determine whether h-apoA-IV plays a protective role after LPS administration. Methods and Results— We injected apoE 0 , h-apoA-IV/E 0 , and C57Bl/6 (wild-type) mice intraperitoneally with either LPS or phosphate-buffered saline (PBS) every week for 10 weeks. Atherosclerotic lesions were significantly smaller in h-apoA-IV/E 0 mice treated with LPS than in their apoE 0 counterparts. The titers of IgG2a and IgG2b autoantibodies to oxidized low-density lipoprotein (LDL) were higher in the LPS-group of h-apoA-IV/E 0 mice than in apoE 0 mice, suggesting that the Th1 response is stronger in the presence of h-apoA-IV. Lymphocytes from the blood, liver, spleen, and thymus of h-apoA-IV/E 0 mice treated with LPS produced less IL-4, INF-γ, and TNF-α proinflammatory cytokines than their apoE 0 counterparts. Furthermore, we demonstrated that recombinant h-apoA-IV blocks the LPS-induced stimulation of monocytes. Conclusions— The expression of h-apoA-IV in apoE 0 mice reduces the susceptibility to atherogenesis and decreases the secretion of proinflammatory cytokines after LPS administration.

We present the characterization of two overlapping human transferrin genomic clones isolated from a liver DNA library. The two clones represent a total length of 24 kilobase pairs and code for 70% of the protein. The

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Myelin deficiency in the central nervous system (CNS) can cause severe disabling conditions. Most of the transgenic mice models overexpressing myelin components have limitations for investigators of myelin deficiency and myelin therapy as they severely alter CNS architecture. It has been postulated that transferrin (Tf) is involved in oligodendrocyte (OL) maturation and myelinogenesis. Because Tf is not an intrinsic myelin constituent, we decided to investigate if its overexpression could have an impact on the myelination process without affecting myelin integrity. We generated transgenic mice containing the complete human Tf gene specifically overexpressed in OLs. This overexpression leads to more than a 30% increase in myelin components, such as galactolipids, phospholipids, and proteins. Electron microscopy showed that myelin is structurally normal in terms of thickness and compaction. Behavior analysis showed that mice do not display significant modifications in their locomotion and cognitive and emotional abilities. Furthermore, in one of the genetic background, animals presented a significant increase in motor coordination. We did not find any modification in OL number during early postnatal development, suggesting that Tf does not act on OL proliferation. In addition, the levels of iron and ferritin remained unchanged in the brain of transgenic mice compared to control mice. Our findings indicate that, besides its known iron transport function, Tf is able to influence myelination process and induce behavioral improvements in mice.

Transferrin (Tf) is the iron-transport protein of vertebrate serum. It is essentially synthesized in the liver, but lower amounts are also produced in other organs, such as testis and brain. A number of studies have been done to characterize the transcriptional elements implicated in the regulation of Tf gene expression in different organs. The results of these studies support the hypothesis that the Tf gene makes use of different combinations of nuclear proteins in different subsets of cells to achieve tissue-specific expression. It is interesting to point out that this occurs in tissues arising from different embryological origin.