Oxidized LDL (oxLDL) activates the angiotensin II type 1 receptor by binding to the lectin-like oxLDL receptor.

Abstract

The angiotensin II type 1 receptor (AT1) is a 7-transmembrane domain GPCR that when activated by its ligand angiotensin II, generates signaling events promoting vascular dysfunction and the development of cardiovascular disease. Here, we show that the single-transmembrane oxidized LDL (oxLDL) receptor (LOX-1) resides in proximity to AT1 on cell-surface membranes and that binding of oxLDL to LOX-1 can allosterically activate AT1-dependent signaling events. oxLDL-induced signaling events in human vascular endothelial cells were abolished by knockdown of AT1 and inhibited by AT1 blockade (ARB). oxLDL increased cytosolic G protein by 350% in Chinese hamster ovary (CHO) cells with genetically induced expression of AT1 and LOX-1, whereas little increase was observed in CHO cells expressing only LOX-1. Immunoprecipitation and in situ proximity ligation assay (PLA) assays in CHO cells revealed the presence of cell-surface complexes involving LOX-1 and AT1. Chimeric analysis showed that oxLDL-induced AT1 signaling events are mediated via interactions between the intracellular domain of LOX-1 and AT1 that activate AT1. oxLDL-induced impairment of endothelium-dependent vascular relaxation of vascular ring from mouse thoracic aorta was abolished by ARB or genetic deletion of AT1. These findings reveal a novel pathway for AT1 activation and suggest a new mechanism whereby oxLDL may be promoting risk for cardiovascular disease.

• Authors: Koichi Yamamoto, Akemi Kakino, Hikari Takeshita, Norihiro Hayashi, Lei Li, Atsushi Nakano, Hiroko Hanasaki-Yamamoto, Yoshiko Fujita, Yuki Imaizumi, Serina Toyama-Yokoyama, Chikako Nakama, Tatsuo Kawai, Masao Takeda, Kazuhiro Hongyo, Ryosuke Oguro, Yoshihiro Maekawa, Norihisa Itoh, Yoichi Takami, Miyuki Onishi, Yasushi Takeya, Ken Sugimoto, Kei Kamide, Hironori Nakagami, Mitsuru Ohishi, Theodore W Kurtz, Tatsuya Sawamura, Hiromi Rakugi
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 8 Pg. 3342-56 (Aug 2015) ISSN: 1530-6860 [Electronic] United States
• PMID: 25877213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Lectins
• Lipoproteins, LDL
• Receptor, Angiotensin, Type 1
• Receptors, Oxidized LDL
• oxidized low density lipoprotein

Topics

• Animals
• CHO Cells
• COS Cells
• Cell Line
• Cell Line, Tumor
• Chlorocebus aethiops
• Cricetulus
• Endothelial Cells (metabolism)
• Endothelium, Vascular (metabolism)
• Humans
• Lectins (metabolism)
• Lipoproteins, LDL (metabolism)
• Receptor, Angiotensin, Type 1 (metabolism)
• Receptors, Oxidized LDL (metabolism)
• Signal Transduction (physiology)