CD40 ligand-dependent tyrosine nitration of prostacyclin synthase in vivo

Article

关键词: SMOOTH-MUSCLE-CELLS;    RADICAL PRODUCTION;    UP-REGULATION;    NITRIC-OXIDE;    PEROXYNITRITE;    ATHEROSCLEROSIS;    ACETYLCHOLINE;    INACTIVATION;    SUPEROXIDE;    PATHOGENESIS;   

DOI  :  10.1161/CIRCULATIONAHA.105.553206

来源: SCIE

【 摘 要 】

Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand, CD40L, but the mechanisms and the mediators by which CD40L contributes to atherosclerosis are poorly defined. Here, we show how CD40L increases vascular inflammation and thrombosis via tyrosine nitration and inhibition of prostacyclin synthase (PGIS), an enzyme with antithrombotic, antiproliferative, and dilatory functions in the normal vasculature. Methods and Results-Exposure of cultured human aortic endothelial cells to clinically relevant concentrations of CD40L ( 20 to 80 ng/mL) dose-dependently increased the production of superoxide (O-2 (.-) ), decreased nitric oxide ( NO) bioactivity, and increased PGIS nitration. Furthermore, inhibition of CD40 expression by small interfering RNA blocked the effects of CD40L on O-2(.-), NO bioactivity, and PGIS nitration, which indicates a specific effect of CD40L. In addition, either depletion of mitochondria (rho(0) cells, ie, mitochondria-depleted cells, to prevent mitochondrial O-2(.-)) or adenoviral overexpression of superoxide dismutase, as well as inhibition of NO synthase, abolished the CD40L-enhanced PGIS nitration, which implies that the mitochondria might be the source of O2(.-) and thus peroxynitrite (ONOO-). Furthermore, SQ29548, a thromboxane A(2)/prostaglandin H-2 receptor antagonist, significantly reduced CD40L-enhanced expression of intercellular adhesion molecule-1. Finally, administration of CD40L resulted in PGIS inhibition and nitration in the aortas of C57BL6 mice but less in mice overexpressing human superoxide dismutase, which suggests that ONOO- might be required for CD40L-enhanced PGIS nitration in vivo. Conclusions-We conclude that CD40L might contribute to the initiation and progression of atherosclerosis by increasing O-2(.-) and ONOO--dependent PGIS nitration and thromboxane A(2)/prostaglandin H-2 receptor stimulation.

【 授权许可】

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