Abstract-Adiponectin is an antiatherogenic adipokine that inhibits inflammation by mechanisms that are not completely understood. We explored the effect of adiponectin on endothelial synthesis of interleukin-8 (IL-8), a pro-inflammatory chemokine that plays a role in atherogenesis. Adiponectin decreased the secretion of IL-8 from human aortic endothelial cells (HAEC) stimulated with tumor necrosis factor-␣ (TNF-␣). Adiponectin also inhibited IL-8 mRNA expression induced by TNF-␣. Phosphorylation of IB-␣ was decreased by adiponectin, but phosphorylation of ERK, SAPK/JNK, and p38MAPK were unaffected. Adiponectin increased intra-cellular cAMP levels in HAEC in a dose-dependent manner; PKA activity was also increased. The inhibitory effect of adiponectin on TNF-␣-induced IL-8 synthesis was inhibited by pretreatment with Rp-cAMP, a PKA inhibitor. These observations suggest that adiponectin inhibits IL-8 synthesis through inhibition of a PKA dependent NF-B signaling pathway. We also showed that adiponectin enhances Akt phosphorylation.

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Several large prospective epidemiological investigations have disclosed that coronary artery disease is the main cause of morbidity and death in patients with diabetes mellitus. The Multiple Risk Factor Intervention Trial [1] revealed that the mortality rate for coronary artery disease and cardiovascular disease such as cerebral infarction and arteriosclerosis obliterans was three times higher in diabetic men than in non-diabetic men.However, the exact cellular and molecular mechanism for increased risk of these atherosclerotic vascular diseases in diabetic patients remains unclear. Atherosclerosis is described as a response of the artery wall to initiating agents followed by the formation of the atherosclerotic plaque by multiple pathogenic mechanisms [2]. One critical pathological event in the atherosclerotic lesion is the migration of medial smooth muscle cells (SMC) to the intima where these cells proliferate. Various molecules regulating SMC growth are secreted from platelets, monocyte/macrophages, lymphocytes, endothelial cells, and SMC themselves. These cells, in concert with a damaged and/or "activated" endothelium, synthesize and release many kinds of growth factors and cytokines, which lead to the migration and proliferation of SMC, the recruitment of additional blood cells, and the accumulation of lipids. Among proinflammatory cytokines, tumour necrosis factor(TNF)-a, interleukin(IL)-1b, IL-6, and IL-8 are reported to be involved in the pathogenesis of atherosclerosis [3].

1 3-Hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) prevent the progression of atherosclerosis by lowering cholesterol. However, the eect of statins on the synthesis of proin¯ammatory cytokines from endothelial cells has not yet been fully investigated. Here, we examined the eect of pravastatin, one of the statins, on IL-8 synthesis induced by thrombin in human aortic endothelial cells (AoEC) cultured with high glucose concentrations. 2 Pravastatin signi®cantly decreased the IL-8 synthesis induced by thrombin. 3 Pravastatin inhibited the p44/42 MAP kinase activity induced by thrombin, but did not inhibit the p38 MAP kinase activity. 4 Translocation of ras protein from the cytosol to plasma membrane was inhibited by pravastatin. 5 Pravastatin inhibit the activator protein-1 activity, but did not inhibit the activation of IkB-a. 6 Dominant negative ras inhibited the p44/42 MAP kinase activity induced by PMA. 7 Our results suggest that pravastatin inhibits IL-8 synthesis by blocking the ras-MAP (p44/42) kinase pathway rather than nuclear factor-kB. Pravastatin may prevent atherosclerosis not only by lowering cholesterol levels, but also by suppressing IL-8 synthesis in AoEC through the inhibition of p44/42 MAP kinase, and this may be more bene®cial in diabetic patients than in non-diabetics.