Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury

Tuoyi Li, Bing Yu, Zhixin Liu, Jingyuan Li, Mingliang Ma, Yingbao Wang, Mingjiang Zhu, Huiyong Yin, Xiaofeng Wang, Yi Fu, Fang Yu, Xian Wang, Xiaohong Fang, Jinpeng Sun () and Wei Kong ()
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Tuoyi Li: Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Bing Yu: Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Zhixin Liu: Shandong University; Key Laboratory Experimental Teratology of the Ministry of Education
Jingyuan Li: CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics
Mingliang Ma: Shandong University; Key Laboratory Experimental Teratology of the Ministry of Education
Yingbao Wang: Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Mingjiang Zhu: Chinese Academy of Sciences (CAS)
Huiyong Yin: Chinese Academy of Sciences (CAS)
Xiaofeng Wang: CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics
Yi Fu: Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Fang Yu: Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Xian Wang: Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Xiaohong Fang: Chinese Academy of Sciences
Jinpeng Sun: Shandong University; Key Laboratory Experimental Teratology of the Ministry of Education
Wei Kong: Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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 Arg167 and Cys289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.

Date: 2018
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DOI: 10.1038/s41467-017-02401-7

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