on August 3, 2006
Published online before print August 3, 2006, doi: 10.1161/01.ATV.0000240050.15321.fe
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Submitted on March 26, 2006
Accepted on June 22, 2006
Angiotensin II Type 1 Receptor-Mediated Inflammation Is Required for Choroidal Neovascularization
Norihiro Nagai ;
From the Laboratory of Retinal Cell Biology (N.N., Y.O., K.I., Y.O., S.I.), Departments of Ophthalmology (N.N., K.I., K.N., Y.O., M.M.I., K.T., S.I.) and Cell Differentiation (N.N., Y.O., T.U., Y.K., T.S.), Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: ishidasu{at}sc.itc.keio.ac.jp.
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-
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--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.
Key words: choroidal neovascularization • inflammation • intercellular adhesion molecule-1 • renin-angiotensin system • vascular endothelial growth factor
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