title: 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: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA kyamamoto@geriat.med.osaka-u.ac.jp ohishi@geriat.med.osaka-u.ac.jp.
authors: Koichi
authors: K
authors: Yamamoto
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Akemi
authors: A
authors: Kakino
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Hikari
authors: H
authors: Takeshita
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Norihiro
authors: N
authors: Hayashi
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Lei
authors: L
authors: Li
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Atsushi
authors: A
authors: Nakano
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Hiroko
authors: H
authors: Hanasaki-Yamamoto
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Yoshiko
authors: Y
authors: Fujita
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Yuki
authors: Y
authors: Imaizumi
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Serina
authors: S
authors: Toyama-Yokoyama
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Chikako
authors: C
authors: Nakama
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Tatsuo
authors: T
authors: Kawai
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Masao
authors: M
authors: Takeda
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Kazuhiro
authors: K
authors: Hongyo
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Ryosuke
authors: R
authors: Oguro
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Yoshihiro
authors: Y
authors: Maekawa
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Norihisa
authors: N
authors: Itoh
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Yoichi
authors: Y
authors: Takami
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Miyuki
authors: M
authors: Onishi
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Yasushi
authors: Y
authors: Takeya
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Ken
authors: K
authors: Sugimoto
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Kei
authors: K
authors: Kamide
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Hironori
authors: H
authors: Nakagami
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA kyamamoto@geriat.med.osaka-u.ac.jp ohishi@geriat.med.osaka-u.ac.jp.
authors: Mitsuru
authors: M
authors: Ohishi
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Theodore W
authors: TW
authors: Kurtz
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Tatsuya
authors: T
authors: Sawamura
authors: *Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan; Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumo, Japan; Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Suita, Osaka, Japan; and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Hiromi
authors: H
authors: Rakugi
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003412:Cricetulus; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D051131:Receptors, Oxidized LDL / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D037102:Lectins; D008077:Lipoproteins, LDL; D044140:Receptor, Angiotensin, Type 1; D051131:Receptors, Oxidized LDL; C099252:oxidized low density lipoprotein
keywords: G protein-coupled receptor; allosteric activation; receptor multimerization; vascular dysfunction