期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02401-7
关键词
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资金
- National Natural Science Foundation of the P.R. China (NSFC) [91539203, 81730010]
- National Key R&D Program of China [2016YFC0903000]
- International Cooperation and Exchanges NSFC [81220108004]
- 111 Project of Chinese Ministry of Education [B07001]
- National Program on Key Basic Research Projects (973 Program) [2012CB518002]
- National Science Fund for distinguished Young Scholars [81225002]
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.
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