動脈硬化血管での炎症制御におけるNOと酸化ストレスの相互作用

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  • The role of nitric oxide and oxidative stress as modulating factors of inflammation in atherosclerosis

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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.<br>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.<br>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.<br>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.<br>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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