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Maria Gomez

Maria Gomez

Professor

Maria Gomez

NFAT regulates the expression of AIF-1 and IRT-1: Yin and yang splice variants of neointima formation and atherosclerosis.

Author

  • Lisa Berglund
  • Olga Kotova
  • Peter Osmark
  • Helena Grufman
  • Chen Xing
  • Marie-Louise Lydrup
  • Isabel Goncalves
  • Michael V Autieri
  • Maria Gomez

Summary, in English

Aims Alternative transcription and splicing of the allograft inflammatory factor-1 (AIF-1) gene results in the expression of two different proteins: AIF-1 and interferon responsive transcript-1 (IRT-1). Here we explore the impact of AIF-1 and IRT-1 on vascular smooth muscle cell (VSMC) activation and neointima formation, the mechanisms underlying their alternative splicing, and associations of AIF-1 and IRT-1 mRNA with parameters defining human atherosclerotic plaque phenotype.Methods and results Translation of AIF-1 and IRT-1 results in different products with contrasting cellular distribution and functions. Overexpression of AIF-1 stimulates migration and proliferation of human VSMCs, whereas IRT-1 exerts opposite effects. Adenoviral infection of angioplasty-injured rat carotid arteries with AdAIF-1 exacerbates intima hyperplasia, whereas infection with AdIRT-1 reduces neointima. Expression of these variants is modulated by changes in nuclear factor of activated T-cells (NFAT) activity. Pharmacological inhibition of NFAT or targeting of NFATc3 with siRNA lowers the AIF-1/IRT-1 ratio and favors an anti-proliferative outcome. NFAT acts as a repressor on the IRT-1 transcriptional start site, which is also sensitive to interferon-γ stimulation. Expression of AIF-1 mRNA in human carotid plaques associates with less extracellular matrix and a more pro-inflammatory plaque and plasma profile, features that may predispose to plaque rupture. In contrast, expression of IRT-1 mRNA associates with a less aggressive phenotype and less VSMCs at the most stenotic region of the plaque.Conclusions Inhibition of NFAT signaling, by shifting the AIF-1/IRT-1 ratio, may be an attractive target to regulate the VSMC response to injury and manipulate plaque stability in atherosclerosis.

Department/s

  • Cardiovascular Research - Immunity and Atherosclerosis
  • Diabetic Complications
  • Genomics, Diabetes and Endocrinology
  • Surgery (Lund)
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2012

Language

English

Pages

414-423

Publication/Series

Cardiovascular Research

Volume

93

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Cardiovascular Research - Immunity and Atherosclerosis
  • Diabetic Complications
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 1755-3245