Angiotensin receptor blocker irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice
Angiotensin receptor blocker irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice
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DOI：
10.1016/j.bbi.2017.11.010
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发表时间：
2018-03-01
影响因子：
15.1
通讯作者：
Takeshita, Kyosuke
中科院分区：
文献类型：
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作者：
Yisireyili, Maimaiti;Uchida, Yasuhiro;Takeshita, Kyosuke
应激与肠易激综合征（IBS）和高血压的病理生理学有关。血管紧张素受体阻滞剂（ARB）通过抑制血管紧张素II（Ang II）/Ang II I型受体轴（AT 1）而具有抗炎特性。经典RAS途径的抑制也涉及血管紧张素转换酶-2（ACE 2）的上调，其激活Ang-（1-7）/Mas途径以抵消炎症信号传导，并作为氨基酸转运蛋白B（0）AT-1的伴侣吸收色氨酸以调节微生物群-肠-脑轴。在这项研究中，我们确定了ARB厄贝沙坦对应激诱导的肠道炎症的影响。对C57 BL/6 J小鼠进行2周间歇性束缚应激。在应激期间，经口给予溶剂、3或10 mg/kg/天厄贝沙坦。束缚应激导致结肠炎症，组织学损伤评分升高，Nox 4、TLR-4和IL 1-β表达增加，活性氧（ROS）积累，ACE血管紧张素II AT 1受体轴激活。应激还下调了肠道氨基酸转运蛋白ACE 2/B（0）AT-1以及肠道哺乳动物雷帕霉素靶蛋白（mTOR）和p70 S6激酶（p70 S6 K）的活性，导致α-防御素减少、肠道微生物内容物变化以及色氨酸代谢紊乱和犬尿氨酸途径激活。厄贝沙坦可抑制应激诱导的All通路的激活，从而减少肠道ROS积聚和炎症，恢复ACE 2/B（0）AT-1的表达、mTOR和p7056 K的活性、微生态失调和色氨酸代谢。我们的研究结果表明，ATI是一个潜在的合适的治疗目标，在应激诱导的肠道炎症，厄贝沙坦可能是有益的，适合于治疗应激IBS患者。(C)2017爱思唯尔公司All rights reserved.
Stress is associated with pathophysiology of both irritable bowel syndrome (IBS) and hypertension. Angiotensin receptor blockers (ARB) have anti-inflammatory properties via inhibition of angiotensin II (Ang II)/Ang II type I receptor axis (AT1). Inhibition of the classical RAS pathway is also involved in upregulation of angiotensin converting enzyme-2 (ACE2), which activates the Ang-(1-7)/Mas pathway to counteract inflammatory signaling and acts as a partner of the amino acid transporter, B(0)AT-1, to absorb tryptophan for regulation of microbiota-gut-brain axis. In this study, we determined the effects of ARB irbesartan on stress-induced intestinal inflammation. C57BL/6J mice were subjected to 2-week intermittent restraint stress. They were orally treated during the stress with either vehicle, 3 or 10 mg/kg/day irbesartan. Restraint stress resulted in colon inflammation with higher histological damage scores, increased expression of Nox4, TLR-4 and IL1-beta, accumulation of reactive oxygen species (ROS), and activation of the ACE angiotensin II AT1 receptor axis. Stress also downregulated intestinal amino acid transporter, ACE2/B(0)AT-1, and activity of intestinal mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K), resulting in decrease in alpha-defensins, changes in intestinal microbial contents, and perturbation of tryptophan metabolism with activation of the kynurenine pathway. Administration of irbesartan inhibited activation of stress-induced All pathway to reduce intestinal ROS accumulation and inflammation, restored expression of ACE2/B(0)AT-1, activity of mTOR and p7056K, dysbiosis and tryptophan metabolism. Our results suggest that ATI is a potentially suitable therapeutic target in stress induced intestinal inflammation, and that irbesartan could be beneficially suitable for the treatment of stressed patients with IBS. (C) 2017 Elsevier Inc. All rights reserved.