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.
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.
Authors: Rene Barro-Soria; Julia Stindl; Claudia Müller; Renate Foeckler; Vladimir Todorov; Hayo Castrop; Olaf Strauß Journal: PLoS One Date: 2012-11-20 Impact factor: 3.240
Authors: Harry A Quigley; Ian F Pitha; Derek S Welsbie; Cathy Nguyen; Matthew R Steinhart; Thao D Nguyen; Mary Ellen Pease; Ericka N Oglesby; Cynthia A Berlinicke; Katherine L Mitchell; Jessica Kim; Joan J Jefferys; Elizabeth C Kimball Journal: PLoS One Date: 2015-10-27 Impact factor: 3.240