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Publications (5)13.5 Total impact

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    Hideyuki Migita, John Morser
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    ABSTRACT: 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma (PPARgamma), has been shown to inhibit proinflammatory gene expression, but the signaling mechanisms involved remain unclear. Because retinoic acid receptor-related orphan receptor-alpha (RORalpha) has been reported to suppress tumor necrosis factor-alpha (TNF-alpha)-induced expression of proinflammatory genes, we hypothesized that 15d-PGJ2 may induce RORalpha expression resulting in inhibition of proinflammatory gene expression. We demonstrate that 15d-PGJ2 induced RORalpha1 and RORalpha4 expression and inhibited TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in human umbilical vein endothelial cells (HUVECs). In contrast, the synthetic PPARgamma ligand pioglitazone weakly induced RORalpha4 expression but did not affect RORalpha1 expression or TNF-alpha-induced gene expression. Biphenol A diglycidyl ether, a PPARgamma antagonist, did not block the effect of 15d-PGJ2 on RORalpha expression. Adenovirus-mediated overexpression of RORalpha1 inhibited TNF-alpha-induced VCAM-1 and ICAM-1 expression, and overexpression of a mutant form of RORalpha1 (RORalpha1Delta), which inhibited transcriptional activity of RORalpha1 and RORalpha4, attenuated its inhibition. Furthermore, we found that RORalpha1Delta attenuated the inhibitory actions of 15d-PGJ2 on TNF-alpha-induced VCAM-1 and ICAM-1 expression. These results suggest that 15d-PGJ2 inhibits TNF-alpha-induced expression of proinflammatory genes mediated in part via induction of RORalpha in HUVECs. This mechanism provides a novel insight into PPARgamma-independent actions of 15d-PGJ2.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2005; 25(4):710-6. · 6.34 Impact Factor
  • Hideyuki Migita, John Morser, Kohichi Kawai
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    ABSTRACT: Rev-erbalpha and retinoic acid receptor-related orphan receptor-alpha (RORalpha) are orphan nuclear receptors but their effects on transcription are opposed. Here, we show that Rev-erbalpha was expressed predominantly in vascular smooth muscle cells (VSMCs) rather than endothelial cells. Overexpression of Rev-erbalpha upregulated the expression of interleukin-6 and cyclooxygenase-2, and increased transactivation by NF-kappaB and translocation of p65 to the nucleus in A7r5 VSMCs. Furthermore, the expression of Rev-erbalpha was upregulated by RORalpha1 but that upregulation was attenuated by Rev-erbalpha itself in A7r5 VSMCs. These results suggest a regulatory link between Rev-erbalpha and the NF-kappaB pathway.
    FEBS Letters 04/2004; 561(1-3):69-74. · 3.58 Impact Factor
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    ABSTRACT: Retinoic acid receptor-related orphan receptor-alpha (RORalpha) is a nuclear orphan receptor. Adenovirus-mediated overexpression of RORalpha1 and RORalpha4 suppressed tumor necrosis factor-alpha (TNF-alpha)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells. Overexpression of RORalpha1 and RORalpha4 also suppressed TNF-alpha-stimulated translocation of p50 and p65 to the nucleus. In contrast, dominant-negative deletion mutants of RORalpha1 and RORalpha4 failed to suppress the induction of VCAM-1 and ICAM-1 and translocations of p50 and p65. These results suggest that RORalpha1 and RORalpha4 regulate the inflammatory responses via inhibition of the nuclear factor-kappaB signaling pathway in endothelial cells.
    FEBS Letters 02/2004; 557(1-3):269-74. · 3.58 Impact Factor
  • Source
    Hideyuki Migita, John Morser, Kohichi Kawai
    [Show abstract] [Hide abstract]
    ABSTRACT: Rev-erbα and retinoic acid receptor-related orphan receptor-α (RORα) are orphan nuclear receptors but their effects on transcription are opposed. Here, we show that Rev-erbα was expressed predominantly in vascular smooth muscle cells (VSMCs) rather than endothelial cells. Overexpression of Rev-erbα upregulated the expression of interleukin-6 and cyclooxygenase-2, and increased transactivation by NF-κB and translocation of p65 to the nucleus in A7r5 VSMCs. Furthermore, the expression of Rev-erbα was upregulated by RORα1 but that upregulation was attenuated by Rev-erbα itself in A7r5 VSMCs. These results suggest a regulatory link between Rev-erbα and the NF-κB pathway.
    Febs Letters - FEBS LETT. 01/2004; 561(1):69-74.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Retinoic acid receptor-related orphan receptor-α (RORα) is a nuclear orphan receptor. Adenovirus-mediated overexpression of RORα1 and RORα4 suppressed tumor necrosis factor-α (TNF-α)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells. Overexpression of RORα1 and RORα4 also suppressed TNF-α-stimulated translocation of p50 and p65 to the nucleus. In contrast, dominant-negative deletion mutants of RORα1 and RORα4 failed to suppress the induction of VCAM-1 and ICAM-1 and translocations of p50 and p65. These results suggest that RORα1 and RORα4 regulate the inflammatory responses via inhibition of the nuclear factor-κB signaling pathway in endothelial cells.
    Febs Letters - FEBS LETT. 01/2004; 557(1):269-274.