Orai1-mediated ICRAC is essential for neointima formation after vascular injury

Wei Zhang, Katharine E. Halligan, Xuexin Zhang, Jonathan M. Bisaillon, José C. Gonzalez-Cobos, Rajender K. Motiani, Guoqing Hu, Peter A. Vincent, Jiliang Zhou, Margarida Barroso, Harold A. Singer, Khalid Matrougui, Mohamed Trebak

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Rationale: The molecular correlate of the calcium release-activated calcium current (ICRAC), 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. Methods and 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 ICRAC 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.

Original languageEnglish (US)
Pages (from-to)534-542
Number of pages9
JournalCirculation research
Volume109
Issue number5
DOIs
Publication statusPublished - Aug 19 2011
Externally publishedYes

    Fingerprint

Keywords

  • CRAC channels
  • calcium channels
  • neointima formation
  • vascular smooth muscle proliferation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Zhang, W., Halligan, K. E., Zhang, X., Bisaillon, J. M., Gonzalez-Cobos, J. C., Motiani, R. K., ... Trebak, M. (2011). Orai1-mediated ICRAC is essential for neointima formation after vascular injury. Circulation research, 109(5), 534-542. https://doi.org/10.1161/CIRCRESAHA.111.246777