The endocytosis of oxidized LDL via the activation of the angiotensin II type 1 receptor
Toshimasa Takahashi,
Yibin Huang,
Koichi Yamamoto,
Go Hamano,
Akemi Kakino,
Fei Kang,
Yuki Imaizumi,
Hikari Takeshita,
Yoichi Nozato,
Satoko Nozato,
Serina Yokoyama,
Motonori Nagasawa,
Tatsuo Kawai,
Masao Takeda,
Taku Fujimoto,
Kazuhiro Hongyo,
Futoshi Nakagami,
Hiroshi Akasaka,
Yoichi Takami,
Yasushi Takeya,
Ken Sugimoto,
Herbert Y. Gaisano,
Tatsuya Sawamura,
Hiromi Rakugi
Affiliations
Toshimasa Takahashi
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada
Yibin Huang
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Koichi Yamamoto
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Corresponding author
Go Hamano
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Akemi Kakino
Department of Molecular Pathophysiology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano 390-8621, Japan
Fei Kang
Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada
Yuki Imaizumi
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Hikari Takeshita
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Yoichi Nozato
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Satoko Nozato
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Serina Yokoyama
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Motonori Nagasawa
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Tatsuo Kawai
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Masao Takeda
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Taku Fujimoto
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Kazuhiro Hongyo
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Futoshi Nakagami
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Hiroshi Akasaka
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Yoichi Takami
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Yasushi Takeya
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Ken Sugimoto
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Herbert Y. Gaisano
Department of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada
Tatsuya Sawamura
Department of Molecular Pathophysiology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano 390-8621, Japan
Hiromi Rakugi
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
Summary: Arrestin-dependent activation of a G-protein-coupled receptor (GPCR) triggers endocytotic internalization of the receptor complex. We analyzed the interaction between the pattern recognition receptor (PRR) lectin-like oxidized low-density lipoprotein (oxLDL) receptor (LOX-1) and the GPCR angiotensin II type 1 receptor (AT1) to report a hitherto unidentified mechanism whereby internalization of the GPCR mediates cellular endocytosis of the PRR ligand. Using genetically modified Chinese hamster ovary cells, we found that oxLDL activates Gαi but not the Gαq pathway of AT1 in the presence of LOX-1. Endocytosis of the oxLDL-LOX-1 complex through the AT1-β-arrestin pathway was demonstrated by real-time imaging of the membrane dynamics of LOX-1 and visualization of endocytosis of oxLDL. Finally, this endocytotic pathway involving GPCR kinases (GRKs), β-arrestin, and clathrin is relevant in accumulating oxLDL in human vascular endothelial cells. Together, our findings indicate that oxLDL activates selective G proteins and β-arrestin-dependent internalization of AT1, whereby the oxLDL-LOX-1 complex undergoes endocytosis.
