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

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.

• Author: Lisa Berglund; Olga Kotova; Peter Osmark; Helena Grufman; Chen Xing; Marie-Louise Lydrup; Isabel Goncalves; Michael V Autieri; Maria Gomez
• Department/s: EXODIAB: Excellence of Diabetes Research in Sweden; Cardiovascular Research - Immunity and Atherosclerosis; Diabetic Complications; Translational Muscle Research; Surgery (Lund); Cardiovascular Research - Translational Studies
• Publishing year: 2012
• Language: English
• Pages: 414-423
• Publication/Series: Cardiovascular Research
• Volume: 93
• Full text: - 13 MB; Download statistics
• Links: http://www.ncbi.nlm.nih.gov/pubmed/22116621?dopt=Abstract; http://dx.doi.org/10.1093/cvr/cvr309
• 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; Cardiovascular Research - Translational Studies
• ISBN/ISSN/Other: ISSN: 1755-3245