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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1531.)
© 2006 American Heart Association, Inc.

Vascular Biology

Therapeutic Potential of a Synthetic Peptide Inhibitor of Nuclear Factor of Activated T Cells as Antirestenotic Agent

Haixiang Yu; Karen Sliedregt-Bol; Herman Overkleeft; Gijs A. van der Marel; Theo J.C. van Berkel; Erik A.L. Biessen

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.

Correspondence to Erik A.L. Biessen, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, the Netherlands. E-mail biessen{at}lacdr.leidenuniv.nl

Objective— The calcineurin/nuclear factor of 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-ß1, stromal cell-derived factor-1, and monocyte chemotactic protein-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 phorbol 12-myristate 13-acetate-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.

Synthetic peptide inhibitor of NFAT selectively and potently inhibits NFAT activation and vSMC proliferation. NFAT and MEK-ERK pathways act in concert to trigger vSMC proliferation. NFAT is the key regulator essential for PDGF-BB-induced vSMC proliferation. VIVIT peptide may lead to more selective and less toxic approaches in antirestenosis therapy.

Key Words: NFAT • restenosis • vSMCs • ERK • peptide inhibitor

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