title: Critical roles of cold shock domain protein A as an endogenous angiogenesis inhibitor in skeletal muscle.
abstract: Angiogenesis is regulated by the local balance between angiogenic stimulators and inhibitors and is maintained by muscle-derived angiogenic factors in ischemic tissues.
  
  
  OBJECTIVE
  Our objectives were to investigate the effect of cold shock domain protein A (CSDA) as an endogenous angiogenesis inhibitor and to develop a novel strategy of therapeutic angiogenesis by blocking CSDA expression.
  
  
  RESULTS
  In human skeletal muscle cells, CSDA was upregulated during hypoxia when cells were damaged and apoptosis was induced. CSDA expression could repress the activity of hypoxia inducible factor-1α and nuclear factor κB, because CSDA can competitively bind the hypoxia response element and the nuclear factor κB-binding element. As a result, vascular endothelial growth factor-A, interleukin-6, and interleukin-8 secretions from skeletal muscle cells were decreased. Further, CSDA depletion increased the secretion level of these angiogenic factors. In a hindlimb ischemia model, transfer of short-hairpin RNA targeting CSDA ameliorated ischemia without direct transfer of angiogenic factors. In this ischemic tissue, vascular endothelial growth factor-A, interleukin-6, and CXCL2 protein levels were increased.
  
  
  CONCLUSIONS
  CSDA appears to play a critical role as an endogenous angiogenesis inhibitor in skeletal muscle, and RNA interference targeting of CSDA is a promising gene therapy strategy for treating peripheral arterial disease.
authors.affiliation: Department of Surgery, Asahikawa Medical University, 2-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, Japan. y-saitou46@nifty.com
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Azuma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirata
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Sasajima
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D060888:Real-Time Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D022762:CCAAT-Enhancer-Binding Proteins; D054426:Chemokine CXCL2; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; C094867:YBX3 protein, human