Thromboxane A2 Regulates Vascular Tone via Its Inhibitory Effect on the Expression of Inducible Nitric Oxide Synthase
Thromboxane A2 Regulates Vascular Tone via Its Inhibitory Effect on the Expression of Inducible Nitric Oxide Synthase
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DOI：
10.1161/01.cir.0000093194.21109.ec
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发表时间：
2003-11
期刊：
影响因子：
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通讯作者：
Takehiro Yamada;T. Fujino;Koh-ichi Yuhki;A. Hara;H. Karibe;O. Takahata;Y. Okada;C. Xiao;K. Takayama;Shuhko Kuriyama;T. Taniguchi;T. Shiokoshi;Y. Ohsaki;K. Kikuchi;S. Narumiya;F. Ushikubi
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文献类型：
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作者：
Takehiro Yamada;T. Fujino;Koh-ichi Yuhki;A. Hara;H. Karibe;O. Takahata;Y. Okada;C. Xiao;K. Takayama;Shuhko Kuriyama;T. Taniguchi;T. Shiokoshi;Y. Ohsaki;K. Kikuchi;S. Narumiya;F. Ushikubi
背景——脓毒症的循环衰竭是由血管反应性低下引起的，其中源自诱导型一氧化氮合酶 (iNOS) 的一氧化氮 (NO) 发挥着主要作用。然而，血栓素 (TX) A2 和 iNOS-NO 系统之间相互作用的细节仍然未知。我们打算通过串扰来阐明 TXA2 在血管反应性低下中的作用。方法和结果——我们检查了培养的血管平滑肌细胞 (VSMC) 中细胞因子诱导的 iNOS 表达和 NO 产生，以及细胞因子诱导的缺乏 TXA2 受体的小鼠（TP−/− 小鼠）主动脉反应性低下。在野生型 VSMC 中观察到的细胞因子诱导的 iNOS 表达和 NO 产生在 TP−/− VSMC 中显着增强，表明内源性 TXA2 对 iNOS 表达的抑制作用。此外，在吲哚美辛处理的野生型 VSMC 中，TP 激动剂 U-46619 以浓度依赖性方式抑制细胞因子诱导的 iNOS 表达和 NO 产生，而 TP−/− VSMC 则没有这种作用。在离体系统中，细胞因子诱导的主动脉对去氧肾上腺素的低反应性在 TP−/− 主动脉中显着增强，但几乎被氨基胍（一种 iNOS 抑制剂）完全消除。因此，TP−/− 主动脉中细胞因子诱导的 NO 产生显着高于野生型主动脉。此外，U-46619 仅在野生型小鼠体内显着抑制脂多糖诱导的体内 NO 产生。结论——这些结果表明，TXA2 在脓毒症等病理条件下通过其对 iNOS-NO 系统的抑制作用，对血管反应性低下的发展具有保护作用。
Background—Circulatory failure in sepsis arises from vascular hyporesponsiveness, in which nitric oxide (NO) derived from inducible NO synthase (iNOS) plays a major role. Details of the cross talk between thromboxane (TX) A2 and the iNOS–NO system, however, remain unknown. We intended to clarify the role of TXA2, via the cross talk, in vascular hyporesponsiveness. Methods and Results—We examined cytokine-induced iNOS expression and NO production in cultured vascular smooth muscle cells (VSMCs) and cytokine-induced hyporesponsiveness of the aorta from mice lacking the TXA2 receptor (TP−/− mice). The cytokine-induced iNOS expression and NO production observed in wild-type VSMCs were significantly augmented in TP−/− VSMCs, indicating an inhibitory effect of endogenous TXA2 on iNOS expression. Furthermore, in indomethacin-treated wild-type VSMCs, U-46619, a TP agonist, inhibited cytokine-induced iNOS expression and NO production in a concentration-dependent manner, effects absent from TP−/− VSMCs. In an ex vivo system, the cytokine-induced hyporesponsiveness of aortas to phenylephrine was significantly augmented in TP−/− aorta but was almost completely canceled by aminoguanidine, an iNOS inhibitor. Accordingly, cytokine-induced NO production was significantly higher in TP−/− aorta than in wild-type aorta. Moreover, U-46619 significantly suppressed lipopolysaccharide-induced NO production in vivo only in wild-type mice. Conclusions—These results suggest that TXA2 has a protective role against the development of vascular hyporesponsiveness via its inhibitory action on the iNOS–NO system under pathological conditions such as sepsis.