PMID- 29296021
OWN - NLM
STAT- MEDLINE
DCOM- 20180212
LR  - 20190102
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 9
IP  - 1
DP  - 2018 Jan 2
TI  - Homocysteine directly interacts and activates the angiotensin II type I receptor 
      to aggravate vascular injury.
PG  - 11
LID - 10.1038/s41467-017-02401-7 [doi]
LID - 11
AB  - Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. 
      However, the mechanism underlying HHcy-aggravated vascular injury remains 
      unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy 
      is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) 
      receptor and in mice treated with an AT1 blocker. We find that homocysteine 
      directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II 
      and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer 
      analysis reveals distinct conformational changes of AT1 receptor upon binding to 
      angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis 
      experiments suggest that homocysteine regulates the conformation of the AT1 
      receptor both orthosterically and allosterically by forming a salt bridge and a 
      disulfide bond with its Arg(167) and Cys(289) residues, respectively. Together, 
      these findings suggest that strategies aimed at blocking the AT1 receptor may 
      mitigate HHcy-associated aneurysmal vascular injuries.
FAU - Li, Tuoyi
AU  - Li T
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
AD  - Capital Normal University High School, Beijing, 100048, China.
FAU - Yu, Bing
AU  - Yu B
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Liu, Zhixin
AU  - Liu Z
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shandong 
      University; Key Laboratory Experimental Teratology of the Ministry of Education, 
      Jinan, Shandong, 250012, China.
FAU - Li, Jingyuan
AU  - Li J
AD  - CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, 
      Institute of High Energy Physics, 19 B, Yuquan Road, Beijing, 100049, China.
FAU - Ma, Mingliang
AU  - Ma M
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shandong 
      University; Key Laboratory Experimental Teratology of the Ministry of Education, 
      Jinan, Shandong, 250012, China.
FAU - Wang, Yingbao
AU  - Wang Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Zhu, Mingjiang
AU  - Zhu M
AD  - Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), 
      Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences 
      (CAS), Shanghai, 200031, China.
FAU - Yin, Huiyong
AU  - Yin H
AUID- ORCID: 0000-0001-7049-1560
AD  - Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), 
      Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences 
      (CAS), Shanghai, 200031, China.
FAU - Wang, Xiaofeng
AU  - Wang X
AD  - CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, 
      Institute of High Energy Physics, 19 B, Yuquan Road, Beijing, 100049, China.
FAU - Fu, Yi
AU  - Fu Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Yu, Fang
AU  - Yu F
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Wang, Xian
AU  - Wang X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Fang, Xiaohong
AU  - Fang X
AD  - Key Laboratory of Molecular Nanostructure and Nanotechnology, CAS 
      Research/Education Center for Excellence in Molecular Sciences, Institute of 
      Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
FAU - Sun, Jinpeng
AU  - Sun J
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shandong 
      University; Key Laboratory Experimental Teratology of the Ministry of Education, 
      Jinan, Shandong, 250012, China. sunjinpeng@sdu.edu.cn.
AD  - School of Medicine, Duke University Medical Center, Durham, NC, 27710, USA. 
      sunjinpeng@sdu.edu.cn.
FAU - Kong, Wei
AU  - Kong W
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China. kongw@bjmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180102
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Receptor, Angiotensin, Type 1)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 11128-99-7 (Angiotensin II)
RN  - 9041-90-1 (Angiotensin I)
SB  - IM
MH  - Allosteric Regulation
MH  - Angiotensin I/metabolism
MH  - Angiotensin II/metabolism
MH  - Animals
MH  - Aortic Aneurysm, Abdominal/*metabolism
MH  - HEK293 Cells
MH  - Homocysteine/*metabolism
MH  - Humans
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Molecular Dynamics Simulation
MH  - Mutagenesis, Site-Directed
MH  - Protein Conformation
MH  - Receptor, Angiotensin, Type 1/*metabolism
MH  - Vascular System Injuries/metabolism
PMC - PMC5750214
COIS- The authors declare no competing financial interests.
EDAT- 2018/01/04 06:00
MHDA- 2018/02/13 06:00
PMCR- 2018/01/02
CRDT- 2018/01/04 06:00
PHST- 2017/02/13 00:00 [received]
PHST- 2017/11/28 00:00 [accepted]
PHST- 2018/01/04 06:00 [entrez]
PHST- 2018/01/04 06:00 [pubmed]
PHST- 2018/02/13 06:00 [medline]
PHST- 2018/01/02 00:00 [pmc-release]
AID - 10.1038/s41467-017-02401-7 [pii]
AID - 2401 [pii]
AID - 10.1038/s41467-017-02401-7 [doi]
PST - epublish
SO  - Nat Commun. 2018 Jan 2;9(1):11. doi: 10.1038/s41467-017-02401-7.