HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/3/C1167    most recent 00590.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Nilsson, L. M. Articles by Gomez, M. F. Search for Related Content PubMed PubMed Citation Articles by Nilsson, L. M. Articles by Gomez, M. F.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation

¹Department of Experimental Medical Science, Lund University, Lund, Sweden; ²Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois; ³Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio; and ⁴Department of Obstetrics and Gynecology and ⁵Department of Surgery, Lund University

Submitted 24 November 2005 ; accepted in final form 30 October 2006

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [³⁵S]methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.

Ca²⁺/calcineurin; endothelin-1; cyclosporin A; contractility; differentiation

This article has been cited by other articles:

				S. de Frutos, L. Duling, D. Alo, T. Berry, O. Jackson-Weaver, M. Walker, N. Kanagy, and L. Gonzalez Bosc NFATc3 is required for intermittent hypoxia-induced hypertension Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2382 - H2390. [Abstract] [Full Text] [PDF]

				S. de Frutos, R. Spangler, D. Alo, and L. V. G. Bosc NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with {alpha}-Actin Up-regulation J. Biol. Chem., May 18, 2007; 282(20): 15081 - 15089. [Abstract] [Full Text] [PDF]