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- Title
"NFAT regulates the alternative splicing of Allograft Inflammatory Factor-1 gene: Role in neointima formation".
- Authors
Nilsson, Lisa M.; Xing, Chen; Bengtsson, Jonas M. E.; Nilsson-Öhman, Jenny; Lydrup, Marie-Louise; Autieri, Michael V.; Gomez, Maria F.
- Abstract
Diabetic patients are more prone to develop restenosis after balloon angioplasty. The underlying pathogenesis is unclear, but hyperglycemia has been suggested as a risk factor. We have recently shown that high-glucose activates the transcription factor NFAT (Nuclear Factor of Activated T cells) c3 in the vasculature and that NFATc3 promotes vascular smooth muscle cell (VSMC) proliferation. Also, NFAT inhibition has earlier been shown to reduce neointima formation. Here we show that NFATc3 regulates the splicing of Allograft Inflammatory Factor-1 (AIF-1). AIF-1 protein increases after angioplasty and is predictive of transplant vasculopathy. Overexpression of AIF-1 stimulates migration and proliferation of VSMCs, whereas its splicing variant IRT-1 exerts the opposite effect. Activation of NFATc3 by high-glucose reduces the expression of IRT-1 in intact arteries, whereas pharmacological inhibition of NFAT or targeting of NFATc3 with siRNA leads to lowered AIF-1/IRT-1 mRNA and protein ratios. Interestingly, adenoviral infection with AIF-1 of carotid arteries after angioplasty exacerbates restenosis, whereas AdIRT-1 yields less neointima. Thus, the NFAT signaling pathway via alternative splicing of AIF-1 may be of importance for the VSMC response to vascular injury. Funding: Swedish Research Council, Swedish Heart & Lung Foundations, National Institutes of Health, American Heart Association.
- Publication
FASEB Journal, 2008, Vol 22, p49
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.22.2_supplement.49