Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization

Norihiro Nagai, Yuichi Oike, Kanako Izumi-Nagai, Takashi Urano, Yoshiaki Kubota, Kousuke Noda, Yoko Ozawa, Makoto Inoue, Kazuo Tsubota, Toshio Suda, Susumu Ishida

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

BACKGROUND - Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration, the most common cause of blindness in the developed countries. The aim of the current study was to determine the involvement of the renin-angiotensin system (RAS) with the development of CNV, using human surgical samples and the murine model of laser-induced CNV. METHODS AND RESULTS - In the human and murine CNV tissues, the vascular endothelium expressed angiotensin II type 1 receptor (AT1-R), AT2-R, and angiotensin II. The CNV volume was significantly suppressed by treatment with an AT1-R blocker telmisartan, but not with an AT2-R blocker. AT1-R signaling blockade with telmisartan inhibited various inflammatory mechanisms including macrophage infiltration and upregulation of VEGF, intercellular adhesion molecule-1 (ICAM-1), MCP-1, and IL-6 in the retinal pigment epithelium-choroid complex. A PPAR-γ antagonist partially but significantly reversed the suppressive effect of telmisartan on in vivo induction of CNV and in vitro upregulation of ICAM-1 and MCP-1 in endothelial cells and IL-6 in macrophages, showing the dual contribution of PPAR-γ-agonistic and AT1-R-antagonistic actions in the telmisartan treatment. CONCLUSIONS - AT1-R-mediated inflammation plays a pivotal role in the development of CNV, indicating the possibility of AT1-R blockade as a novel therapeutic strategy to inhibit CNV.

Original languageEnglish
Pages (from-to)2252-2259
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume26
Issue number10
DOIs
Publication statusPublished - 2006 Oct

Fingerprint

Choroidal Neovascularization
Angiotensin Type 1 Receptor
Inflammation
Peroxisome Proliferator-Activated Receptors
Intercellular Adhesion Molecule-1
Interleukin-6
Up-Regulation
Macrophages
Angiotensin II Type 1 Receptor Blockers
Choroid
Retinal Pigment Epithelium
Vascular Endothelium
Macular Degeneration
Blindness
Renin-Angiotensin System
Developed Countries
Angiotensin II
Vascular Endothelial Growth Factor A
Lasers
Endothelial Cells

Keywords

  • Choroidal neovascularization
  • Inflammation
  • Intercellular adhesion molecule-1
  • Renin-angiotensin system
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization. / Nagai, Norihiro; Oike, Yuichi; Izumi-Nagai, Kanako; Urano, Takashi; Kubota, Yoshiaki; Noda, Kousuke; Ozawa, Yoko; Inoue, Makoto; Tsubota, Kazuo; Suda, Toshio; Ishida, Susumu.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26, No. 10, 10.2006, p. 2252-2259.

Research output: Contribution to journalArticle

Nagai, Norihiro ; Oike, Yuichi ; Izumi-Nagai, Kanako ; Urano, Takashi ; Kubota, Yoshiaki ; Noda, Kousuke ; Ozawa, Yoko ; Inoue, Makoto ; Tsubota, Kazuo ; Suda, Toshio ; Ishida, Susumu. / Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2006 ; Vol. 26, No. 10. pp. 2252-2259.
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T1 - Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization

AU - Nagai, Norihiro

AU - Oike, Yuichi

AU - Izumi-Nagai, Kanako

AU - Urano, Takashi

AU - Kubota, Yoshiaki

AU - Noda, Kousuke

AU - Ozawa, Yoko

AU - Inoue, Makoto

AU - Tsubota, Kazuo

AU - Suda, Toshio

AU - Ishida, Susumu

PY - 2006/10

Y1 - 2006/10

N2 - BACKGROUND - Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration, the most common cause of blindness in the developed countries. The aim of the current study was to determine the involvement of the renin-angiotensin system (RAS) with the development of CNV, using human surgical samples and the murine model of laser-induced CNV. METHODS AND RESULTS - In the human and murine CNV tissues, the vascular endothelium expressed angiotensin II type 1 receptor (AT1-R), AT2-R, and angiotensin II. The CNV volume was significantly suppressed by treatment with an AT1-R blocker telmisartan, but not with an AT2-R blocker. AT1-R signaling blockade with telmisartan inhibited various inflammatory mechanisms including macrophage infiltration and upregulation of VEGF, intercellular adhesion molecule-1 (ICAM-1), MCP-1, and IL-6 in the retinal pigment epithelium-choroid complex. A PPAR-γ antagonist partially but significantly reversed the suppressive effect of telmisartan on in vivo induction of CNV and in vitro upregulation of ICAM-1 and MCP-1 in endothelial cells and IL-6 in macrophages, showing the dual contribution of PPAR-γ-agonistic and AT1-R-antagonistic actions in the telmisartan treatment. CONCLUSIONS - AT1-R-mediated inflammation plays a pivotal role in the development of CNV, indicating the possibility of AT1-R blockade as a novel therapeutic strategy to inhibit CNV.

AB - BACKGROUND - Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration, the most common cause of blindness in the developed countries. The aim of the current study was to determine the involvement of the renin-angiotensin system (RAS) with the development of CNV, using human surgical samples and the murine model of laser-induced CNV. METHODS AND RESULTS - In the human and murine CNV tissues, the vascular endothelium expressed angiotensin II type 1 receptor (AT1-R), AT2-R, and angiotensin II. The CNV volume was significantly suppressed by treatment with an AT1-R blocker telmisartan, but not with an AT2-R blocker. AT1-R signaling blockade with telmisartan inhibited various inflammatory mechanisms including macrophage infiltration and upregulation of VEGF, intercellular adhesion molecule-1 (ICAM-1), MCP-1, and IL-6 in the retinal pigment epithelium-choroid complex. A PPAR-γ antagonist partially but significantly reversed the suppressive effect of telmisartan on in vivo induction of CNV and in vitro upregulation of ICAM-1 and MCP-1 in endothelial cells and IL-6 in macrophages, showing the dual contribution of PPAR-γ-agonistic and AT1-R-antagonistic actions in the telmisartan treatment. CONCLUSIONS - AT1-R-mediated inflammation plays a pivotal role in the development of CNV, indicating the possibility of AT1-R blockade as a novel therapeutic strategy to inhibit CNV.

KW - Choroidal neovascularization

KW - Inflammation

KW - Intercellular adhesion molecule-1

KW - Renin-angiotensin system

KW - Vascular endothelial growth factor

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