Yu Haixiang, Sliedregt-Bol Karen, Overkleeft Herman, van der Marel Gijs A, van Berkel Theo J C, Biessen Erik A L
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, Netherlands.
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1531-7. doi: 10.1161/01.ATV.0000225286.30710.af. Epub 2006 May 4.
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.
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-beta1, stromal cell-derived factor-1alpha, and monocyte chemotactic protein-1 expression in vSMCs. Unlike FK506 or CsA, VIVIT did not affect nuclear factor kappaB 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.
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.
钙调神经磷酸酶/活化T细胞核因子（NFAT）轴在调节血管平滑肌细胞（vSMC）增殖和炎症的关键基因方面发挥着关键作用，这使得抑制NFAT成为预防再狭窄的一种有吸引力的方式。
合成肽VIVIT能有效抑制RAW 264.7巨噬细胞、Ea.Hy.926内皮细胞和vSMC中的NFAT激活，并阻断离子霉素诱导的NFAT核转位。VIVIT以及环孢素A（CsA）或他克莫司（FK506）完全抑制血小板衍生生长因子-BB（PDGF-BB）和凝血酶诱导的vSMC增殖。此外，它还显著抑制vSMC中PDGF-BB和凝血酶诱导的白细胞介素-6、白细胞介素-8、转化生长因子-β1、基质细胞衍生因子-1α和单核细胞趋化蛋白-1的表达。与FK506或CsA不同，VIVIT不影响核因子κB报告基因的激活，并且在体外仅对内皮伤口愈合有轻微影响。VIVIT不干预佛波酯12-肉豆蔻酸酯13-乙酸酯刺激的细胞外信号调节激酶激活（证实了其对NFAT的特异性）。此外，我们的数据证实NFAT是PDGF-BB诱导的vSMC增殖的调节因子。
VIVIT似乎是NFAT激活以及NFAT介导的增殖和炎症的一种特异性强效抑制剂。与FK506或CsA不同，合成的VIVIT疗法不会伴随对钙调神经磷酸酶信号传导的非NFAT介导的副作用，并且在抗再狭窄治疗中是一个有前景的先导药物。
