title: Orai1-mediated I (CRAC) is essential for neointima formation after vascular injury.
abstract: BACKGROUND
  The molecular correlate of the calcium release-activated calcium current (I(CRAC)), the channel protein Orai1, is upregulated in proliferative vascular smooth muscle cells (VSMC). However, the role of Orai1 in vascular disease remains largely unknown.
  
  
  OBJECTIVE
  The goal of this study was to determine the role of Orai1 in neointima formation after balloon injury of rat carotid arteries and its potential upregulation in a mouse model of VSMC remodeling.
  
  
  RESULTS
  Lentiviral particles encoding short-hairpin RNA (shRNA) targeting either Orai1 (shOrai1) or STIM1 (shSTIM1) caused knockdown of their respective target mRNA and proteins and abrogated store-operated calcium entry and I(CRAC) in VSMC; control shRNA was targeted to luciferase (shLuciferase). Balloon injury of rat carotid arteries upregulated protein expression of Orai1, STIM1, and calcium-calmodulin kinase IIdelta2 (CamKIIδ2); increased proliferation assessed by Ki67 and PCNA and decreased protein expression of myosin heavy chain in medial and neointimal VSMC. Incubation of the injured vessel with shOrai1 prevented Orai1, STIM1, and CamKIIδ2 upregulation in the media and neointima; inhibited cell proliferation and markedly reduced neointima formation 14 days post injury; similar results were obtained with shSTIM1. VSMC Orai1 and STIM1 knockdown inhibited nuclear factor for activated T-cell (NFAT) nuclear translocation and activity. Furthermore, Orai1 and STIM1 were upregulated in mice carotid arteries subjected to ligation.
  
  
  CONCLUSIONS
  Orai1 is upregulated in VSMC during vascular injury and is required for NFAT activity, VSMC proliferation, and neointima formation following balloon injury of rat carotids. Orai1 provides a novel target for control of VSMC remodeling during vascular injury or disease.
authors: Center for Cardiovascular Sciences, Albany Medical College, Mail Code 8, 47 New Scotland Ave, Albany, NY 12208, USA.
authors: Wei
authors: W
authors: Zhang
authors: Katharine E
authors: KE
authors: Halligan
authors: Xuexin
authors: X
authors: Zhang
authors: Jonathan M
authors: JM
authors: Bisaillon
authors: José C
authors: JC
authors: Gonzalez-Cobos
authors: Rajender K
authors: RK
authors: Motiani
authors: Guoqing
authors: G
authors: Hu
authors: Peter A
authors: PA
authors: Vincent
authors: Jiliang
authors: J
authors: Zhou
authors: Margarida
authors: M
authors: Barroso
authors: Harold A
authors: HA
authors: Singer
authors: Khalid
authors: K
authors: Matrougui
authors: Mohamed
authors: M
authors: Trebak
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D002404:Catheterization / Q000009:adverse effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000071740:ORAI1 Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D015220:Calcium Channels; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat