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These data provide evidence that APE1/ref-1 in endothelial cells mitigates TNF-alpha-induced monocyte adhesion and expression of vascular cell adhesion molecules, and this anti-adhesive property of APE1/ref-1 is primarily mediated by a NOS-dependent mechanism. Furthermore, APE1/ref-1 may inhibit VCAM-1 expression by inhibiting superoxide production and p38 MAPK activation.

Key Words: apurinic/apyrimidinic endonuclease-1/redox factor-1 Ⅲ vascular smooth muscle cells Ⅲ migration Ⅲ reactive oxygen species Ⅲ spleen tyrosine kinase P latelet-derived growth factor (PDGF) performs crucial functions in the regulation of vascular cell proliferation and migration, resulting in circulatory disorders including atherosclerosis. PDGF stimulates intracellular signal molecules with Src homology 2 (SH2) domains, including Src, phospholipase C, phosphatidylinositol 3-kinase (PI3K), and ras/raf-1. 1,2 Src, PI3K, and phospholipase C␥ perform crucial functions related to actin reorganization, growth, and migration in response to PDGF in the vascular smooth muscle cells, 3 and these activities are mediated by the activation of a family of serine/threonine-specific protein kinases, the mitogen-activated protein kinases (MAPK), most notably p38 MAPK. 4 Recently, we determined that spleen tyrosine kinase (Syk), a 70-kDa non-receptor protein tyrosine kinase harboring 2 SH2 domains, binds to phosphorylated PDGF receptor (PDGF-R) and contributes to PDGF-mediated migration in the vascular smooth muscle. 5 Moreover, PDGF-R transmits its signal into intracellular space with the production of reactive oxygen species (ROS), particularly superoxide (O 2 Ϫ⅐ ) and hydrogen peroxide (H 2 O 2 ). 6,7 PDGF augments O 2 Ϫ⅐ levels through NADPH oxidase (NOX), and the inhibition of NOX activity reduces PDGF-induced chemotaxis in vascular smooth muscle cells. 8,9 Because ROS perform crucial functions in many aspects of cellular function, the redox system can be implicated in the regulation of vascular dysfunction. Furthermore, ROS stimulates PDGF-R phosphorylation. 10 These results indicate that ROS may be involved in the activation of PDGF-R via ROS-activated protein kinases.

To examine the role of p66shc in endothelial dysfunction, we investigated the endothelium-dependent relaxation, protein expression and superoxide production in abdominal aortic coarctation rats. Endothelium-dependent relaxation to acetylcholine was impaired only in the aortic segments above the aortic coarctation (35.0±7.1% vs. 86.6 ± 6.0% for sham control at 1 lM Ach). The aortic segments exposed to increased blood pressure showed a decreased phosphorylation of endothelial nitric oxide synthase, an increased phosphorylation of p66shc, and an increased superoxide production. Angiotensin II elicited a significantly increased phosphorylation of p66shc in the endothelial cells. Taken together, these findings suggest that the increased phosphorylation of p66shc is one of the important mediators in the impaired endothelium-dependent relaxation of aortic coarctation rats.

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