title: The actin-binding protein Girdin and its Akt-mediated phosphorylation regulate neointima formation after vascular injury.
abstract: BACKGROUND
  It is well established that the migration and proliferation of vascular smooth muscle cells (VSMCs) have major roles in the vascular remodeling process. Our previous study showed that the Akt substrate Girdin, which is expressed in VSMCs and endothelial cells, is essential for postnatal angiogenesis. However, the function of Girdin and its Akt-mediated phosphorylation in VSMCs and their in vivo roles in vascular remodeling remain to be elucidated.
  
  
  OBJECTIVE
  We investigated the function of Girdin and its Akt-mediated phosphorylation using cultured VSMCs and animal models of vascular remodeling.
  
  
  RESULTS
  The depletion of Girdin by RNA interference disrupted the rearrangement of the actin cytoskeleton in VSMCs, resulting in impaired cell migration. The depletion of Girdin also inhibited VSMC proliferation. Girdin expression was highly upregulated and its serine at position 1416 was phosphorylated in the neointima of carotid arteries after balloon injury in a rat model. The introduction of an adenovirus harboring short hairpin RNA against Girdin attenuated the proliferation of VSMCs and neointima formation without affecting reendothelialization. Furthermore, we found that neointima formation after femoral wire injury was significantly attenuated in Girdin S1416A knock-in mice, in which the Akt phosphorylation site of Girdin was mutated, thus indicating a major role for Girdin phosphorylation in vascular remodeling.
  
  
  CONCLUSIONS
  These findings indicate that Girdin and its Akt-mediated phosphorylation have major roles in the migration and proliferation of VSMCs and vascular remodeling, making the Akt/Girdin signaling pathway a potential target for the development of new therapeutics for vascular diseases.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Kengo
authors.initials: K
authors.lastname: Maeda
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichimiya
authors.forename: Mayu
authors.initials: M
authors.lastname: Isotani-Sakakibara
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yamamura
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000209:etiology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D005263:Femoral Artery / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D008840:Microfilament Proteins; D051057:Proto-Oncogene Proteins c-akt; D033921:Vesicular Transport Proteins; C527550:Ccdc88a protein, mouse