PMID- 29155324
OWN - NLM
STAT- MEDLINE
DCOM- 20190415
LR  - 20201209
IS  - 1090-2139 (Electronic)
IS  - 0889-1591 (Linking)
VI  - 69
DP  - 2018 Mar
TI  - Angiotensin receptor blocker irbesartan reduces stress-induced intestinal 
      inflammation via AT1a signaling and ACE2-dependent mechanism in mice.
PG  - 167-179
LID - S0889-1591(17)30511-1 [pii]
LID - 10.1016/j.bbi.2017.11.010 [doi]
AB  - 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 AT1 
      pathway to reduce intestinal ROS accumulation and inflammation, restored 
      expression of ACE2/B(0)AT-1, activity of mTOR and p70S6K, dysbiosis and 
      tryptophan metabolism. Our results suggest that AT1 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.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Yisireyili, Maimaiti
AU  - Yisireyili M
AD  - Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, 
      Japan; Department of Minimally Invasive Hernia and Abdominal Wall Surgery, 
      People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830000, Xinjiang 
      Uygur Autonomous Region, China.
FAU - Uchida, Yasuhiro
AU  - Uchida Y
AD  - Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, 
      Japan.
FAU - Yamamoto, Koji
AU  - Yamamoto K
AD  - Department of Transfusion Medicine and Cell Therapy, Saitama Medical Centre, 
      Saitama Medical University, Kawagoe, Japan.
FAU - Nakayama, Takayuki
AU  - Nakayama T
AD  - Department of Blood Transfusion, Aichi Medical University Hospital, Nagakute, 
      Japan.
FAU - Cheng, Xian Wu
AU  - Cheng XW
AD  - Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, 
      Japan.
FAU - Matsushita, Tadashi
AU  - Matsushita T
AD  - Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan; 
      Department of Blood Transfusion, Nagoya University Hospital, Nagoya, Japan.
FAU - Nakamura, Shigeo
AU  - Nakamura S
AD  - Department of Pathology, Nagoya University Hospital, Nagoya, Japan.
FAU - Murohara, Toyoaki
AU  - Murohara T
AD  - Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, 
      Japan.
FAU - Takeshita, Kyosuke
AU  - Takeshita K
AD  - Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, 
      Japan; Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, 
      Japan. Electronic address: kyousuke@med.nagoya-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171116
PL  - Netherlands
TA  - Brain Behav Immun
JT  - Brain, behavior, and immunity
JID - 8800478
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptor, Angiotensin, Type 1)
RN  - EC 3.4.15.1 (Peptidyl-Dipeptidase A)
RN  - EC 3.4.17.23 (Ace2 protein, mouse)
RN  - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
RN  - J0E2756Z7N (Irbesartan)
SB  - IM
MH  - Angiotensin II Type 1 Receptor Blockers/pharmacology/*therapeutic use
MH  - Angiotensin-Converting Enzyme 2
MH  - Animals
MH  - Inflammation/*drug therapy/metabolism
MH  - Intestinal Mucosa/metabolism
MH  - Intestines/*drug effects
MH  - Irbesartan/pharmacology/*therapeutic use
MH  - Mice
MH  - Peptidyl-Dipeptidase A/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Receptor, Angiotensin, Type 1/*metabolism
MH  - Restraint, Physical
MH  - Signal Transduction/drug effects
MH  - Stress, Physiological/drug effects
MH  - Stress, Psychological/*metabolism
OTO - NOTNLM
OT  - Intestinal inflammation
OT  - Micro-biota
OT  - Reactive oxygen species
OT  - Renin-angiotensinogen system
OT  - Stress
OT  - Tryptophan metabolism
EDAT- 2017/11/21 06:00
MHDA- 2019/04/16 06:00
CRDT- 2017/11/21 06:00
PHST- 2017/06/07 00:00 [received]
PHST- 2017/11/02 00:00 [revised]
PHST- 2017/11/15 00:00 [accepted]
PHST- 2017/11/21 06:00 [pubmed]
PHST- 2019/04/16 06:00 [medline]
PHST- 2017/11/21 06:00 [entrez]
AID - S0889-1591(17)30511-1 [pii]
AID - 10.1016/j.bbi.2017.11.010 [doi]
PST - ppublish
SO  - Brain Behav Immun. 2018 Mar;69:167-179. doi: 10.1016/j.bbi.2017.11.010. Epub 2017 
      Nov 16.