Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Faculty of Medicine, University of Sydney, Sydney, Australia.
Nat Med. 2010 Mar;16(3):279-85. doi: 10.1038/nm.2092. Epub 2010 Feb 28.
Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.
血管张力的控制是血管稳态的核心。在这里，我们表明内皮细胞中表达的色氨酸到犬尿氨酸的色氨酸 2,3-双加氧酶 (Ido) 的代谢有助于动脉血管松弛和血压控制。疟原虫（疟原虫）感染或内毒素血症诱导的小鼠内皮细胞表达 Ido，导致血浆色氨酸浓度降低，犬尿氨酸浓度增加和低血压。Ido 的药理学抑制增加了全身性炎症小鼠的血压，但在缺乏 Ido 或干扰素-γ（Ido 诱导所需）的小鼠中则没有增加。色氨酸和犬尿氨酸均使预先收缩的猪冠状动脉扩张；色氨酸的扩张作用需要活性 Ido 和完整的内皮细胞的存在，而犬尿氨酸的作用则与内皮无关。犬尿氨酸诱导的动脉松弛是通过激活腺嘌呤核苷酸和可溶性鸟苷酸环化酶途径介导的。犬尿氨酸给药以剂量依赖性方式降低自发性高血压大鼠的血压。我们的结果确定了 Ido 介导的色氨酸代谢是调节血管张力的新途径。
