Dietary factors, especially fat composition, influence the progression of insulin resistance and metabolic disorders. Using a rat model of type II diabetes (Otsuka Long-Evans Tokushima Fatty (OLETF)), we examined the effects of fatty acid composition on insulin-mediated whole-body glucose uptake using hyperinsulinemic euglycemic clamp technique. Rats were fed powdered chow (5.1% fat) with the addition of 1.0g/kg/day of eicosapentaenoic-(94% eicosapentaenoic acid, EPA) or oleic-rich (79% oleic acid, OA) oils from 5 weeks until 30 weeks of age. EPA-rich diet, but not the OA-rich diet, significantly improved insulin sensitivity and decreased concentrations of plasma and liver lipids and abdominal fat deposition. Whole body insulin sensitivity was significantly inversely correlated with plasma triglyceride levels. Oral glucose tolerance test tended to be improved in the EPA group compared to that in the other two groups, although the difference was not significant. These results indicate that long-term feeding of EPA, but not with OA, may have a beneficial effect on insulin sensitivity in type II diabetes mellitus.

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Increasing numbers of evidence suggests the involvement of inflammation in the pathogenesis of atherosclerosis. Among many substances produced in vascular wall, nitric oxide (NO) regulates endothelial functions and maintains vascular integrity, whereas oxidative stress such as superoxide serves to promote inflammation. Under the physiological condition, NO is produced by endothelial NO synthase (eNOS) in response to vascular shear stress and agonist stimulation. In atherosclerotic vessels, the production of nitric oxide (NO) is decreased and oxidative stress is increased. We investigated the roles of nitric oxide as an anti-inflammatory factor and clarify the source of superoxide production in human atherosclerotic coronary arteries.
NO inhibits leukocyte adhesion to endothelial cells in vitro. This inhibition is associated with reduced expressions of endothelial adhesion molecules such as ICAM-1 and VCAM-1. We investigated whether endogenous NO exerts anti-inflammatory actions in vivo using transgenic mice overexpressing eNOS (eNOS-Tg) in vascular endothelium, which we developed. As an inflammation model, we used lipopolysaccharide (LPS)-induced lung injury model. LPS caused prominent inflammatory changes in lung, which were attenuated in eNOS-Tg. In eNOS-Tg, leukocyte infiltration in lung was markedly reduced and expressions of ICAM-1 and VCAM-1 mRNAs were significantly attenuated compared to those in wild type mice. Thus, endogenous NO actually abates inflammation in vivo. In atheroscelerotic vessels, there are upregulation of endothelial adhesion molecules and the presence of activated NFkB is also demonstrated. Thus, the reduced NO production is likely to exaggerate the inflammatory process in those vessels.
Next we examined the expression of NADH/NADPH oxidase in atherosclerotic human coronary arteries obtained at autopsy. Several lines of evidence shows that NADH/NADPH oxidase system is the major source of superoxide production in vessels. Immunohistochemistory revealed that the p22 phox, a critical component of this oxidase, was expressed in human coronary arteries and the expression was seen in infiltrating macrophages, advential fibroblasts, neointimal and medial vascular smooth muscle cells and endothelial cells. Those expressions were more intense in atherosclerotic arteries than in non-atherosclerotic arteries. Given the importance of oxidative stress, upregulated p22 phox may participate in the process of atherosclerosis.
Recent studies showed that the beneficial effects of HMG CoA reductase inhibitors (HMGCoARIs) on atherosclerosis are partly mediated by their antiinflammatory actions. HMGCoARIs are demonstrated to inhibit leukocyte-endothelial adhesion. On the other hand, HMGCoARIs increases eNOS expressions and NO production in endothelial cells. This effects is mediated by blocking of Rho geranylgeranylation. We found that cerivastatin, a HMGCoARI, inhibits LPS-induced upregulation of ICAM-1 mRNA and the effect is independent of its NO-producing action. Thus, HMGCoARIs exhibit anti-inflammatory action via both NO-dependent and -independent manners.
In conclusion, from the point of inflammation, the therapeutic strategy to increase NO and suppress oxidative stress is required for prevention and treatment of atherosclerosis.

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Virus infection as a pathogen in human vascular diseases has been an important and unsolved issue to be studied. According to Koch's postulates, several conditions should be met to define an organism as a pathogen of human disease: especially, 1) to confirm the whole or a part of structure of microorganism including genomic DNA or RNA in the human material, 2) whether infection of microorganism can induce similar disease in mammals. Several bacterias such as Chlamydia pneumoniae or Hericobactor pylori have been studied according to these postulates, however, it has been hazardous for virus research to establish animal model due to species-specificity or tropism. Human cytomegalovirus (HCMV) is one of these candidates, and HCMV DNA has been frequently detected in the both normal and disordered aorta, however, it is sure that presence of viral genome does not always imply its pathogenecity. As important evidences indicating the pathogenesity of HCMV in human vascular diseases, our recent studies demonstrated virus-specific gene transcription in the surgical specimens of “inflammatory” aortic aneurysms but not in any other human aortic tissue, and also exhibited that the immediate early (IE) gene product stimulates vascular smooth muscle proliferation in rabbit carotid arteries. Whereas these findings suggest the pathogenic ability of HCMV in human vascular tree, some issues to be sollved including the reason why HCMV-IE does not induce any inflammatory response in rabbit. Clearly the immune system is varied among the species and this point should be studied very carefully. Overall, although it seems nearly slow, we consider that the studies for virus etiology in human vascular disorders are now getting progression.

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Takayasu arteritis is a chronic inflammatory disease that mainly involves the aorta and its main branches. The inflammatory process in the early stage consists of infiltration of lymphocytes and monocytes predominantly into the adventitia and outer third of the media.
Our recent national survey of the patients of Takayasu arteritis (n=897) in 1998 revealed that the most patients were in their SOs, which was different from the first survey in 1978 in which it was those in their 20s. On the contrary, our survey still showed that the average age of the onset of the disease in female patients was in their 20s, which was the same as in the previous survey.
Episodes of ischemic heart disease, dissecting aneurysm and rupture of the aorta are increasing in Takayasu arteritis patients even in those still in the 40s or 50s Histological examination confirms the progression of atherosclerotic lesions in the distracted fibrous media caused by Takayasu arteritis even if the patients are free from other risk factors for atherosclerosis such as hypertension, hyperlipidemia, diabetes mellitus, and smoking.
These results suggest the improvement of the prognosis of Takayasu arteritis is due to early diagnosis and treatment of the arteritis and, at the same time, the arteritis causes the increase of atherosclerotic disorders. Therefore, inflammation caused by the arteritis could be another risk factor for causeing and accelerating atherosclerosis.

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