Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Biol. Chem. 279 (11): 10702-10709

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation

ROLE OF CALCIUM, ENDOTHELIUM-DERIVED NITRIC OXIDE, AND cGMP-DEPENDENT PROTEIN KINASE*

Laura V. Gonzalez Bosc, Michael K. Wilkerson, Karen N. Bradley{ddagger}, Delrae M. Eckman§, David C. Hill-Eubanks, , and Mark T. Nelson¶

Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont 05405 and {ddagger}Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom

Abstract: The transcription factor NFAT (nuclear factor of activated T-cells) is implicated in cardiac hypertrophy and vasculogenesis. NFAT activation, reflecting dephosphorylation by the calcium-dependent phosphatase, calcineurin, and subsequent nuclear localization, is generally thought to require a sustained increase in intracellular calcium. However, in smooth muscle we have found that elevation of calcium by membrane depolarization fails to induce an increase in nuclear localization of the NFATc3 isoform. Here, we demonstrate that physiological intravascular pressure (100 mm Hg) induces an increase in NFATc3 nuclear localization in mouse cerebral arteries. Pressure-induced NFATc3 nuclear accumulation is abrogated by endothelial denudation and by nitric-oxide synthase, cGMP-dependent kinase (PKG), and voltage-dependent calcium channels inhibition. We further show that exogenous nitric oxide, in combination with an elevation in calcium, is an effective stimulus for NFATc3 nuclear accumulation. c-Jun terminal kinase 2 (JNK) activity, which has been shown to regulate NFATc3 nuclear export, is also reduced by pressure, an effect that is prevented by pretreatment with a PKG inhibitor. Consistent with this, pressure-induced NFATc3 nuclear accumulation is independent of PKG in arteries from JNK2-/- mice. Collectively, our results indicate that both activation of the NO/PKG pathway and elevation of smooth muscle calcium are required for NFATc3 nuclear accumulation and that PKG inhibits JNK2 to decrease NFAT nuclear export. Our findings suggest that at physiological intravascular pressures NFATc3 is localized to the nucleus in smooth muscle cells of intact arteries and indicate a novel and unexpected role for nitric oxide/PKG in NFAT activation.


Received for publication November 26, 2003. Revision received December 17, 2003.

* This work was supported by National Institutes of Health Grants HL44455, HL63722, and DDK53832(to M. T. N.), HL07647-12 (a postdoctoral cardiovascular training grant to D. C. H.-E.), and HL07944 (a postdoctoral training grant to M. K. W.), American Heart Association Postdoctoral Fellowship 022559713 (to L. V. G. B.), Grant PG/2001079 from the British Heart Foundation and Novartis Foundation (to K. N. B.), and by a grant from the Totman Trust for Medical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Wake Forest University Health Sciences, Dept. of Pediatrics, Division of Neonatology, Winston-Salem, NC 27157.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405. Tel.: 802-656-2500; Fax: 802-656-4523; E-mail: mark.nelson{at}uvm.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
NFAT is required for spontaneous pulmonary hypertension in superoxide dismutase 1 knockout mice.
J. M. Ramiro-Diaz, C. H. Nitta, L. D. Maston, S. Codianni, W. Giermakowska, T. C. Resta, and L. V. G. Bosc (2013)
Am J Physiol Lung Cell Mol Physiol 304, L613-L625
   Abstract »    Full Text »    PDF »
NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice.
R. Bierer, C. H. Nitta, J. Friedman, S. Codianni, S. de Frutos, J. A. Dominguez-Bautista, T. A. Howard, T. C. Resta, and L. V. Gonzalez Bosc (2011)
Am J Physiol Lung Cell Mol Physiol 301, L872-L880
   Abstract »    Full Text »    PDF »
Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries.
S. de Frutos, J. M. Ramiro Diaz, C. H. Nitta, M. L. Sherpa, and L. V. Gonzalez Bosc (2011)
Am J Physiol Cell Physiol 301, C441-C450
   Abstract »    Full Text »    PDF »
NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice.
S. de Frutos, E. Caldwell, C. H. Nitta, N. L. Kanagy, J. Wang, W. Wang, M. K. Walker, and L. V. Gonzalez Bosc (2010)
Am J Physiol Heart Circ Physiol 299, H356-H363
   Abstract »    Full Text »    PDF »
Isoform- and tissue-specific regulation of the Ca2+-sensitive transcription factor NFAT in cardiac myocytes and heart failure.
A. Rinne, N. Kapur, J. D. Molkentin, S. M. Pogwizd, D. M. Bers, K. Banach, and L. A. Blatter (2010)
Am J Physiol Heart Circ Physiol 298, H2001-H2009
   Abstract »    Full Text »    PDF »
Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia.
L. M. Nilsson-Berglund, A. V. Zetterqvist, J. Nilsson-Ohman, M. Sigvardsson, L. V. Gonzalez Bosc, M.-L. Smith, A. Salehi, E. Agardh, G. N. Fredrikson, C.-D. Agardh, et al. (2010)
Arterioscler Thromb Vasc Biol 30, 218-224
   Abstract »    Full Text »    PDF »
Mechanoregulation of Proliferation.
X. Jiang, P. F. Austin, R. A. Niederhoff, S. R. Manson, J. J. Riehm, B. L. Cook, G. Pengue, K. Chitaley, K. Nakayama, K. I. Nakayama, et al. (2009)
Mol. Cell. Biol. 29, 5104-5114
   Abstract »    Full Text »    PDF »
Regulation of soluble guanylyl cyclase-{alpha}1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR.
S. de Frutos, C. H. Nitta, E. Caldwell, J. Friedman, and L. V. Gonzalez Bosc (2009)
Am J Physiol Lung Cell Mol Physiol 297, L475-L486
   Abstract »    Full Text »    PDF »
High blood pressure arising from a defect in vascular function.
S. K. Michael, H. K. Surks, Y. Wang, Y. Zhu, R. Blanton, M. Jamnongjit, M. Aronovitz, W. Baur, K. Ohtani, M. K. Wilkerson, et al. (2008)
PNAS 105, 6702-6707
   Abstract »    Full Text »    PDF »
NFATc3 is required for intermittent hypoxia-induced hypertension.
S. de Frutos, L. Duling, D. Alo, T. Berry, O. Jackson-Weaver, M. Walker, N. Kanagy, and L. Gonzalez Bosc (2008)
Am J Physiol Heart Circ Physiol 294, H2382-H2390
   Abstract »    Full Text »    PDF »
Nitric oxide facilitates NFAT-dependent transcription in mouse myotubes.
J. A. Drenning, V. A. Lira, C. G. Simmons, Q. A. Soltow, J. E. Sellman, and D. S. Criswell (2008)
Am J Physiol Cell Physiol 294, C1088-C1095
   Abstract »    Full Text »    PDF »
Activity-dependent NFATc3 nuclear accumulation in pericytes from cortical parenchymal microvessels.
J. A. Filosa, M. T. Nelson, and L. V. Gonzalez Bosc (2007)
Am J Physiol Cell Physiol 293, C1797-C1805
   Abstract »    Full Text »    PDF »
NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with {alpha}-Actin Up-regulation.
S. de Frutos, R. Spangler, D. Alo, and L. V. G. Bosc (2007)
J. Biol. Chem. 282, 15081-15089
   Abstract »    Full Text »    PDF »
Activation of NFATc3 Down-regulates the beta1 Subunit of Large Conductance, Calcium-activated K+ Channels in Arterial Smooth Muscle and Contributes to Hypertension.
M. Nieves-Cintron, G. C. Amberg, C. B. Nichols, J. D. Molkentin, and L. F. Santana (2007)
J. Biol. Chem. 282, 3231-3240
   Abstract »    Full Text »    PDF »
The cGMP/Protein Kinase G Pathway Contributes to Dihydropyridine-sensitive Calcium Response and Cytokine Production in TH2 Lymphocytes.
B. Gomes, M. Savignac, M. D. Cabral, P. Paulet, M. Moreau, C. Leclerc, R. Feil, F. Hofmann, J.-C. Guery, G. Dietrich, et al. (2006)
J. Biol. Chem. 281, 12421-12427
   Abstract »    Full Text »    PDF »
Excitation-Transcription Coupling in Arterial Smooth Muscle.
B. R. Wamhoff, D. K. Bowles, and G. K. Owens (2006)
Circ. Res. 98, 868-878
   Abstract »    Full Text »    PDF »
High Glucose Activates Nuclear Factor of Activated T Cells in Native Vascular Smooth Muscle.
J. Nilsson, L. M. Nilsson, Y.-W. Chen, J. D. Molkentin, D. Erlinge, and M. F. Gomez (2006)
Arterioscler Thromb Vasc Biol 26, 794-800
   Abstract »    Full Text »    PDF »
Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated signaling pathway that controls myoblast fusion.
A. Pisconti, S. Brunelli, M. Di Padova, C. De Palma, D. Deponti, S. Baesso, V. Sartorelli, G. Cossu, and E. Clementi (2006)
J. Cell Biol. 172, 233-244
   Abstract »    Full Text »    PDF »
Function of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion.
F. Hofmann, R. Feil, T. Kleppisch, and J. Schlossmann (2006)
Physiol Rev 86, 1-23
   Abstract »    Full Text »    PDF »
Excitation-transcription coupling in smooth muscle.
C. A. Barlow, P. Rose, R. A. Pulver-Kaste, and K. M. Lounsbury (2006)
J. Physiol. 570, 59-64
   Abstract »    Full Text »    PDF »
Constrictor-induced translocation of NFAT3 in human and rat pulmonary artery smooth muscle.
A. Yaghi and S. M. Sims (2005)
Am J Physiol Lung Cell Mol Physiol 289, L1061-L1074
   Abstract »    Full Text »    PDF »
Nuclear Factor of Activated T Cells and Serum Response Factor Cooperatively Regulate the Activity of an {alpha}-Actin Intronic Enhancer.
L. V. G. Bosc, J. J. Layne, M. T. Nelson, and D. C. Hill-Eubanks (2005)
J. Biol. Chem. 280, 26113-26120
   Abstract »    Full Text »    PDF »
Stretch of the Vascular Wall Induces Smooth Muscle Differentiation by Promoting Actin Polymerization.
S. Albinsson, I. Nordstrom, and P. Hellstrand (2004)
J. Biol. Chem. 279, 34849-34855
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882