Suppression of choroidal neovascularization hy inhibiting angiotensin-converting enzyme

Minimal role of bradykinin

Norihiro Nagai, Yuichi Oike, Kanako Izumi-Nagai, Takashi Koto, Shingo Satofuka, Hajime Shinoda, Kousuke Noda, Yoko Ozawa, Makoto Inoue, Kazuo Tsubota, Susumu Ishida

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38 Citations (Scopus)

Abstract

PURPOSE. Angiotensin-Converting enzyme (ACE), also known as kininase II, functions not only to convert angiotensin I to angiotensin II, but also to cleave bradykinin into inactive fragments. Thus, ACE inhibition causes the tissue accumulation of bradykinin, exerting either of two opposite effects: anti- or proangiogenic. The purpose of the present study was to investigate the role of bradykinin in the development of choroidal neovascularization (CNV), with or without ACE inhibition. METHODS. Laser photocoagulation was used to induce CNV in wild-type C57BL/6J mice and angiotensin II type 1 receptor (AT1-R)-deficient mice. Wild-type mice were pretreated with the ACE inhibitor Imidapril, with or without the bradykinin B2 receptor (B2-R) antagonist icatibant daily for 6 days before photocoagulation, and the treatment was continued daily until the end of the study. CNV response was analyzed by volumetric measurements using confocal microscopy 1 week after laser injury. The mRNA and protein levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM)-1, and monocyte chemotactic protein (MCP)-1 in the retinal pigment epithelium- choroid complex were examined by RT-PCR and ELISA, respectively. RESULTS. ACE inhibition led to significant suppression of CNV development to the level seen in AT1-R-deficient mice. B2-R blockade together with high-dose but not low-dose ACE inhibition resulted in more potent suppression of CNV than did ACE inhibition alone. B2-R blockade alone exhibited little or no effect on CNV. VEGF, ICAM-1, and MCP-1 levels, elevated by CNV induction, were significantly suppressed by ACE inhibition. VEGF but not ICAM-1 or MCP-1 levels were further attenuated by B2-R blockade with ACE inhibition. CONCLUSIONS. These results suggest a limited contribution of the kallikrein-kinin system to the pathogenesis of CNV, in which the renin-angiotensin system plays more essential roles for facilitating angiogenesis. The present study indicates the possibility of ACE inhibition as a novel therapeutic strategy to inhibit CNV.

Original languageEnglish
Pages (from-to)2321-2326
Number of pages6
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number5
DOIs
Publication statusPublished - 2007 May

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Choroidal Neovascularization
Bradykinin
Peptidyl-Dipeptidase A
Chemokine CCL2
Intercellular Adhesion Molecule-1
Vascular Endothelial Growth Factor A
Angiotensin Type 1 Receptor
Light Coagulation
Lasers
Kallikrein-Kinin System
Angiotensin I
Choroid
Retinal Pigment Epithelium
Renin-Angiotensin System
Inbred C57BL Mouse
Angiotensin-Converting Enzyme Inhibitors
Confocal Microscopy
Angiotensin II
Enzyme-Linked Immunosorbent Assay
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Ophthalmology

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Suppression of choroidal neovascularization hy inhibiting angiotensin-converting enzyme : Minimal role of bradykinin. / Nagai, Norihiro; Oike, Yuichi; Izumi-Nagai, Kanako; Koto, Takashi; Satofuka, Shingo; Shinoda, Hajime; Noda, Kousuke; Ozawa, Yoko; Inoue, Makoto; Tsubota, Kazuo; Ishida, Susumu.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 5, 05.2007, p. 2321-2326.

Research output: Contribution to journalArticle

Nagai, Norihiro ; Oike, Yuichi ; Izumi-Nagai, Kanako ; Koto, Takashi ; Satofuka, Shingo ; Shinoda, Hajime ; Noda, Kousuke ; Ozawa, Yoko ; Inoue, Makoto ; Tsubota, Kazuo ; Ishida, Susumu. / Suppression of choroidal neovascularization hy inhibiting angiotensin-converting enzyme : Minimal role of bradykinin. In: Investigative Ophthalmology and Visual Science. 2007 ; Vol. 48, No. 5. pp. 2321-2326.
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author = "Norihiro Nagai and Yuichi Oike and Kanako Izumi-Nagai and Takashi Koto and Shingo Satofuka and Hajime Shinoda and Kousuke Noda and Yoko Ozawa and Makoto Inoue and Kazuo Tsubota and Susumu Ishida",
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T1 - Suppression of choroidal neovascularization hy inhibiting angiotensin-converting enzyme

T2 - Minimal role of bradykinin

AU - Nagai, Norihiro

AU - Oike, Yuichi

AU - Izumi-Nagai, Kanako

AU - Koto, Takashi

AU - Satofuka, Shingo

AU - Shinoda, Hajime

AU - Noda, Kousuke

AU - Ozawa, Yoko

AU - Inoue, Makoto

AU - Tsubota, Kazuo

AU - Ishida, Susumu

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N2 - PURPOSE. Angiotensin-Converting enzyme (ACE), also known as kininase II, functions not only to convert angiotensin I to angiotensin II, but also to cleave bradykinin into inactive fragments. Thus, ACE inhibition causes the tissue accumulation of bradykinin, exerting either of two opposite effects: anti- or proangiogenic. The purpose of the present study was to investigate the role of bradykinin in the development of choroidal neovascularization (CNV), with or without ACE inhibition. METHODS. Laser photocoagulation was used to induce CNV in wild-type C57BL/6J mice and angiotensin II type 1 receptor (AT1-R)-deficient mice. Wild-type mice were pretreated with the ACE inhibitor Imidapril, with or without the bradykinin B2 receptor (B2-R) antagonist icatibant daily for 6 days before photocoagulation, and the treatment was continued daily until the end of the study. CNV response was analyzed by volumetric measurements using confocal microscopy 1 week after laser injury. The mRNA and protein levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM)-1, and monocyte chemotactic protein (MCP)-1 in the retinal pigment epithelium- choroid complex were examined by RT-PCR and ELISA, respectively. RESULTS. ACE inhibition led to significant suppression of CNV development to the level seen in AT1-R-deficient mice. B2-R blockade together with high-dose but not low-dose ACE inhibition resulted in more potent suppression of CNV than did ACE inhibition alone. B2-R blockade alone exhibited little or no effect on CNV. VEGF, ICAM-1, and MCP-1 levels, elevated by CNV induction, were significantly suppressed by ACE inhibition. VEGF but not ICAM-1 or MCP-1 levels were further attenuated by B2-R blockade with ACE inhibition. CONCLUSIONS. These results suggest a limited contribution of the kallikrein-kinin system to the pathogenesis of CNV, in which the renin-angiotensin system plays more essential roles for facilitating angiogenesis. The present study indicates the possibility of ACE inhibition as a novel therapeutic strategy to inhibit CNV.

AB - PURPOSE. Angiotensin-Converting enzyme (ACE), also known as kininase II, functions not only to convert angiotensin I to angiotensin II, but also to cleave bradykinin into inactive fragments. Thus, ACE inhibition causes the tissue accumulation of bradykinin, exerting either of two opposite effects: anti- or proangiogenic. The purpose of the present study was to investigate the role of bradykinin in the development of choroidal neovascularization (CNV), with or without ACE inhibition. METHODS. Laser photocoagulation was used to induce CNV in wild-type C57BL/6J mice and angiotensin II type 1 receptor (AT1-R)-deficient mice. Wild-type mice were pretreated with the ACE inhibitor Imidapril, with or without the bradykinin B2 receptor (B2-R) antagonist icatibant daily for 6 days before photocoagulation, and the treatment was continued daily until the end of the study. CNV response was analyzed by volumetric measurements using confocal microscopy 1 week after laser injury. The mRNA and protein levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM)-1, and monocyte chemotactic protein (MCP)-1 in the retinal pigment epithelium- choroid complex were examined by RT-PCR and ELISA, respectively. RESULTS. ACE inhibition led to significant suppression of CNV development to the level seen in AT1-R-deficient mice. B2-R blockade together with high-dose but not low-dose ACE inhibition resulted in more potent suppression of CNV than did ACE inhibition alone. B2-R blockade alone exhibited little or no effect on CNV. VEGF, ICAM-1, and MCP-1 levels, elevated by CNV induction, were significantly suppressed by ACE inhibition. VEGF but not ICAM-1 or MCP-1 levels were further attenuated by B2-R blockade with ACE inhibition. CONCLUSIONS. These results suggest a limited contribution of the kallikrein-kinin system to the pathogenesis of CNV, in which the renin-angiotensin system plays more essential roles for facilitating angiogenesis. The present study indicates the possibility of ACE inhibition as a novel therapeutic strategy to inhibit CNV.

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