title: Direct Renin Inhibition with Aliskiren Improves Ischemia-Induced Neovasculogenesis in Diabetic Animals via the SDF-1 Related Mechanism.
abstract: OBJECTIVE
  Aliskiren is a direct renin inhibitor which is suggested to modify proangiogenic cells in addition to lower blood pressure. Given that angiogenesis is impaired in the presence of diabetes mellitus, we would like to investigate whether and how aliskiren enhances endothelial progenitor cells (EPCs) and improves ischemic-induced neovasculogenesis by an effect independent of blood pressure reduction in diabetic animals.
  
  
  METHODS
  Streptozotocin-induced diabetic mice were administered with either aliskiren (5 or 25 mg/kg/day) using an osmotic pump or hydralazine (2 or 10 mg/kg/day) given in drinking water for two weeks prior to a hind-limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively.
  
  
  RESULTS
  In streptozotocin-induced diabetic mice, aliskiren enhanced the recovery of limb perfusion and capillary density, increased the number of circulating Sca-1+/Flk-1+ EPC-like cells, and elevated the levels of the plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α in a dose-dependent manner, whereas there were no such effects in hydralazine-treated mice. Intraperitoneal administration of anti-SDF-1 neutralizing monoclonal antibodies abolished the effects of aliskiren.
  
  
  CONCLUSIONS
  Independent of the reduction of blood pressure, aliskiren enhanced ischemia-induced neovasculogenesis in a dose-dependent manner via VEGF/SDF-1α related mechanisms in diabetic mice.
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors: Ting-Ting
authors: TT
authors: Chang
authors: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors: Tao-Cheng
authors: TC
authors: Wu
authors: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors: Po-Hsun
authors: PH
authors: Huang
authors: Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors: Chih-Pei
authors: CP
authors: Lin
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, R.O.C; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors: Jia-Shiong
authors: JS
authors: Chen
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, R.O.C; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors: Liang-Yu
authors: LY
authors: Lin
authors: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors: Shing-Jong
authors: SJ
authors: Lin
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, R.O.C; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors: Jaw-Wen
authors: JW
authors: Chen
mesh_terms: D000577:Amides / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D066026:Endothelial Progenitor Cells / Q000187:drug effects*; D005650:Fumarates / Q000008:administration & dosage; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage; D007511:Ischemia / Q000503:physiopathology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000911:Antibodies, Monoclonal; D054377:Chemokine CXCL12; D005650:Fumarates; D006830:Hydralazine; D042461:Vascular Endothelial Growth Factor A; D000092502:Renin Inhibitors; C515256:Cxcl12 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C446481:aliskiren