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, Wei Kong

Journal: Nature communications 2018;9(1):11

PMID: 29296021

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

Address: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China.; Capital Normal University High School, Beijing, 100048, China.; Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University; Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, 250012, China.; CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, 19 B, Yuquan Road, Beijing, 100049, China.; 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.; 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.; Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University; Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, 250012, China. [email protected].; School of Medicine, Duke University Medical Center, Durham, NC, 27710, USA. [email protected].; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China. [email protected].

DOI: 10.1038/s41467-017-02401-7

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MeSH Terms: Allosteric Regulation, Angiotensin I, Angiotensin II, Animals, Aortic Aneurysm, Abdominal, HEK293 Cells, Homocysteine, Humans, Male, Mice, Inbred C57BL, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Protein Conformation, Receptor, Angiotensin, Type 1, Vascular System Injuries