title: Suppression of choroidal neovascularization by inhibiting angiotensin-converting enzyme: minimal role of bradykinin.
abstract: OBJECTIVE
  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: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan.
authors: Norihiro
authors: N
authors: Nagai
authors: Yuichi
authors: Y
authors: Oike
authors: Kanako
authors: K
authors: Izumi-Nagai
authors: Takashi
authors: T
authors: Koto
authors: Shingo
authors: S
authors: Satofuka
authors: Hajime
authors: H
authors: Shinoda
authors: Kousuke
authors: K
authors: Noda
authors: Yoko
authors: Y
authors: Ozawa
authors: Makoto
authors: M
authors: Inoue
authors: Kazuo
authors: K
authors: Tsubota
authors: Susumu
authors: S
authors: Ishida
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D065094:Bradykinin B2 Receptor Antagonists; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D048289:Imidazolidines / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016234:Kallikrein-Kinin System / Q000502:physiology; D017075:Laser Coagulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D065094:Bradykinin B2 Receptor Antagonists; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D048289:Imidazolidines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D018799:Intercellular Adhesion Molecule-1; C065679:icatibant; C065166:imidapril; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin