on May 4, 2006
Published online before print May 4, 2006, doi: 10.1161/01.ATV.0000225286.30710.af
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Submitted on December 1, 2005
Accepted on April 18, 2006
Therapeutic Potential of a Synthetic Peptide Inhibitor of Nuclear Factor of Activated T Cells as Antirestenotic Agent
Haixiang Yu ;
From the Division of Biopharmaceutics (H.Y., T.J.C.v., E.A.L.B.), Leiden/Amsterdam Center for Drug Research, Leiden University, the Netherlands; and Leiden Institute of Chemistry (K.S., H.O., G.A.v.), Gorlaeus Laboratories, Leiden University, the Netherlands.
* To whom correspondence should be addressed. E-mail: biessen{at}lacdr.leidenuniv.nl.
Objective--The calcineurin/nuclear factor of the activated T cells (NFAT) axis plays a pivotal role in the regulation of critical genes in vascular smooth muscle cell (vSMC) proliferation and inflammation, which makes NFAT inhibition an attractive modality in the prevention of restenosis.
Methods and Results--Synthetic peptide VIVIT potently inhibited NFAT activation in RAW 264.7 macrophages, Ea.Hy.926 endothelial cells, and vSMCs and blocked ionomycin-elicited nuclear import of NFAT. VIVIT, as well as cyclosporine A (CsA) or FK506, completely blunted platelet-derived growth factor-BB (PDGF-BB) and thrombin-induced vSMC proliferation. Moreover, it significantly inhibited PDGF-BB and thrombin-induced interleukin-6, interleukin-8, transforming growth factor-
1, stromal cell-derived factor-1
, and MCP-1 expression in vSMCs. Unlike FK506 or CsA, VIVIT did not affect nuclear factor 
B reporter gene activation and did only marginally affect endothelial wound healing in vitro. VIVIT did not intervene in PMA-stimulated extracellular signal-regulated kinase activation, confirming its specificity for NFAT. Furthermore, our data establish that NFAT is a regulator of PDGF-BB induced vSMC proliferation.
Conclusions--VIVIT appears to be a specific and potent inhibitor of NFAT activation and thus of NFAT-mediated proliferation and inflammation. Unlike FK506 or CsA, synthetic VIVIT therapy will not be accompanied by non-NFAT-mediated side effects on calcineurin signaling and constitutes a promising lead in antirestenotic therapy.
Key words: NFAT • restenosis • vSMCs • ERK • peptide inhibitor
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