title: NFAT regulates the expression of AIF-1 and IRT-1: yin and yang splice variants of neointima formation and atherosclerosis.
abstract: OBJECTIVE
  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.
  
  
  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 small interfering RNA (siRNA) lowers the AIF-1/IRT-1 ratio and favours 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 signalling, 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.
authors: Department of Clinical Sciences,  Lund University, CRC, Entrance 72, Building 91, Level 12, 205 02 Malmö,  Sweden.
authors: Lisa M
authors: LM
authors: Berglund
authors: Olga
authors: O
authors: Kotova
authors: Peter
authors: P
authors: Osmark
authors: Helena
authors: H
authors: Grufman
authors: Chen
authors: C
authors: Xing
authors: Marie-Louise
authors: ML
authors: Lydrup
authors: Isabel
authors: I
authors: Goncalves
authors: Michael V
authors: MV
authors: Autieri
authors: Maria F
authors: MF
authors: Gomez
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D002135:Calcium-Binding Proteins; D002339:Carotid Arteries / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023903:Coronary Restenosis / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009215:Myometrium / Q000098:blood supply; D050778:NFATC Transcription Factors / Q000378:metabolism*; D058426:Neointima / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human