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A Molecular Cascade Showing Nitric Oxide-Heme Oxygenase-1-Vascular Endothelial Growth Factor-Interleukin-8 Sequence in Human Endothelial Cells

Department of Microbiology and Immunology (H.-O.P., G.-S.O., B.-M.C., H.-T.C.), Wonkwang University School of Medicine, Iksan-Shi, Chonbug 570-749, Republic of Korea; and Vascular System Research Center and Department of Molecular and Cellular Biochemistry (Y.-M.K.), Kangwon National University School of Medicine, Chunchon, Kangwon-Do 200-701, Republic of Korea

Address all correspondence and requests for reprints to: Hun-Taeg Chung, M.D., Ph.D., Department of Microbiology and Immunology, Wonkwang University School of Medicine, 344-2 Shinyoung-Dong, Iksan-Shi, Chonbug 570-749, Republic of Korea. E-mail: htchung{at}wonkwang.ac.kr.

Heme oxygenase (HO)-1 has been shown to be an important biological target of nitric oxide (NO). NO can induce HO-1 expression and IL-8 production, particularly, in endothelial cells. Interestingly, HO-1 tends to induce the production of vascular endothelial growth factor (VEGF) that is involved in endothelial IL-8 syntheses. Whether HO-1 expression by NO may provide a link with IL-8 or VEGF synthesis was investigated in human umbilical vein endothelial cells (HUVECs). The NO donor S-nitroso-N-acetyl-penicillamine (SNAP) dose-dependently increased IL-8 and VEGF productions and HO-1 expression in HUVECs. Transfection with either HO-1 small interfering RNA or HO-1 antisense oligodeoxynucleotide abrogated the ability of SNAP to induce HO-1 expression and IL-8 and VEGF productions. Both pharmacological induction and gene transfer of HO-1 directly induced IL-8 and VEGF productions. Anti-VEGF neutralizing antibody blocked SNAP-mediated IL-8 production and VEGF itself induced IL-8 production, whereas anti-IL-8 neutralizing antibody had no effect on VEGF production in SNAP-treated HUVECs. Neither anti-VEGF nor anti-IL-8 antibodies influenced SNAP-induced HO-1 expression. Moreover, neither VEGF nor IL-8 showed an additive effect on SNAP-induced HO-1 expression. HO-1 transfection had no significant effect on productions of other CXC chemokines, such as growth-related oncogen- and epithelial neutrophil activation peptide-78. Taken together, these results provide a molecular cascade showing NO-HO-1-VEGF-IL-8 sequence in human endothelial cells.

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