Cell Biochemistry and Biophysics

, Volume 43, Issue 3, pp 439–449 | Cite as

Cytoskeletal regulation of nitric oxide synthase

Review Article

Abstract

The three isoforms of nitric oxide synthase (NOS)—endothelial NOS (eNOS), inducible NOS (iNOS), and neural NOS (nNOS)—colocalize with the cytoskeleton including actin microfilaments, microtubules, and intermediate filaments directly or indirectly. These colocalizations enable optimal nitric oxide production and help NOS exert their functions. The reorganization of cytoskeletal polymerization state induced by extracellular stimuli such as shear stress, hypoxia, and drugs regulates eNOS, nNOS, and iNOS. Alterations of nitric oxide production caused by cytoskeletal reorganization play an important role in physiological and pathophysiological conditions. This review focuses on recent data regarding the regulation of NOS by the cytoskeleton at transcriptional, posttranscriptional, and posttranslational levels.

Index Entries

Actin microtubules intermediate filaments endothelium transcription 

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References

  1. 1.
    Moncada, S. and Higgs A. (1993) The L-argininenitric oxide pathway. N. Engl. J. Med. 329, 2002–2012.PubMedCrossRefGoogle Scholar
  2. 2.
    Michel, T. and Feron, O. (1997) Nitric oxide synthases: which, where, how, and why? J. Clin. Invest. 100, 2146–2152.PubMedGoogle Scholar
  3. 3.
    dos Remedios, C. G., Chhabra, D., Kekic, M., Dedova, I. V., Tsubakihara, M., Berry, D. A., and Nosworthy, N. J. (2003) Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol. Rev. 83, 433–473.PubMedGoogle Scholar
  4. 4.
    Mounier, N. and Arrigo, A. P. (2002) Actin cytoskeleton and small heat shock proteins: how do they interact? Cell Stress Chaperones 7, 167–176.PubMedCrossRefGoogle Scholar
  5. 5.
    Lee, T. Y. and Gotlieb, A. I. (2003) Microfilaments and microtubules maintain endothelial integrity. Microsc. Res. Tech. 60, 115–127.PubMedCrossRefGoogle Scholar
  6. 6.
    Dudek, S. M. and Garcia, J. G. (2001) Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91, 1487–1500.PubMedGoogle Scholar
  7. 7.
    Wade, R. H., Meurer-Grob, P., Metoz, F., and Arnal, I. (1998) Organisation and structure of microtubules and microtubule-motor protein complexes. Eur. Biophys. J. 27, 446–454.PubMedCrossRefGoogle Scholar
  8. 8.
    Kreis, T. E. (1990) Role of microtubules in the organisation of the Golgi apparatus. Cell Motil. Cytoskeleton 15, 67–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Helfand, B. T., Chang, L., and Goldman, R. D. (2003) The dynamic and motile properties of intermediate filaments. Annu. Rev. Cell Dev. Biol. 19, 445–467.PubMedCrossRefGoogle Scholar
  10. 10.
    Davies, P. F. (1995) Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75, 519–560.PubMedGoogle Scholar
  11. 11.
    Cucina, A., Sterpetti, A. V., Pupelis, G., Fragale, A., Lepidi, S., Cavallaro, A., Giustiniani, Q., and Santoro, D. L. (1995) Shear stress induces changes in the morphology and cytoskeleton organisation of arterial endothelial cells. Eur. J. Vasc. Endovasc. Surg. 9, 86–92.PubMedCrossRefGoogle Scholar
  12. 12.
    Kim, D. W., Gotlieb, A. I., and Langille, B. L. (1989) In vivo modulation of endothelial F-actin microfilaments by experimental alterations in shear stress. Arteriosclerosis 9, 439–445.PubMedGoogle Scholar
  13. 13.
    Lehoux, S. and Tedgui, A. (2003) Cellular mechanics and gene expression in blood vessels. J. Biomech. 36, 631–643.PubMedCrossRefGoogle Scholar
  14. 14.
    Hutcheson, I. R. and Griffith, T. M. (1996) Mechanotransduction through the endothelial cytoskeleton: mediation of flow—but not agonist-induced EDRF release. Br. J. Pharmacol. 118, 720–726.PubMedGoogle Scholar
  15. 15.
    Skidgel, R. A. (2002) Proliferation of regulatory mechanisms for eNOS: an emerging role for the cytoskeleton. Am. J. Physiol. Lung Cell Mol. Physiol. 282, L1179-L1182.PubMedGoogle Scholar
  16. 16.
    Henrion, D., Terzi, F., Matrougui, K., Duriez, M., Boulanger, C. M., Colucci-Guyon, E., Babinet, C., Briand, P., Friedlander, G., Poitevinet, P., and Levy, B. I. (1997) Impaired flow-induced dilation in mesenteric resistance arteries from mice lacking vimentin. J. Clin. Invest. 100, 2909–2914.PubMedCrossRefGoogle Scholar
  17. 17.
    Papapetropoulos, A., Rudic, R. D., and Sessa, W. C. (1999) Molecular control of nitric oxide synthases in the cardiovascular system. Cardiovasc. Res. 43, 509–520.PubMedCrossRefGoogle Scholar
  18. 18.
    Li, H., Wallerath, T., and Forstermann, U. (2002) Physiological mechanisms regulating the expression of endothelial-type NO synthase. Nitric Oxide 7, 132–147.PubMedCrossRefGoogle Scholar
  19. 19.
    Yoshizumi, M., Perrella, M. A., Burnett, Jr. J. C., and Lee, M. E. (1993) Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ. Res. 73, 205–209.PubMedGoogle Scholar
  20. 20.
    Searles, C. D., Miwa, Y., Harrison, D. G., and Ramasamy, S. (1999) Posttranscriptional regulation of endothelial nitric oxide synthase during cell growth. Circ. Res. 85, 588–595.PubMedGoogle Scholar
  21. 21.
    Laufs, U., Endres, M., Stagliano, N., Amin-Hanjani, S., Chui, D. S., Yang, S. X., Simoncini, T., Yamada, M., Rabkin, E., Allen, P. G., Huang, P. L., Bohm, M., Schoen, F. J., Moskowitz, M. A., and Liao, J. K. (2000) Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J. Clin. Invest. 106, 15–24.PubMedGoogle Scholar
  22. 22.
    Takemoto, M., Sun, J., Hiroki, J., Shimokawa, H., and Liao, J. K. (2002) Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 106, 57–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Su, Y., Edwards-Bennett, S., Bubb, M. R., and Block, E. R. (2003) Regulation of endothelial nitric oxide synthase by the actin cytoskeleton. Am. J. Physiol. Cell Physiol. 284, C1542-C1549.PubMedGoogle Scholar
  24. 24.
    Nasmyth, K. and Jansen, R. P. (1997) The cytoskeleton in mRNA localization and cell differentiation. Curr. Opin. Cell. Biol. 9, 396–400.PubMedCrossRefGoogle Scholar
  25. 25.
    Bassell, G. J. and Singer, R. H. (2001) Neuronal RNA localization and the cytoskeleton. Results Probl. Cell Differ. 34, 41–56.PubMedGoogle Scholar
  26. 26.
    Bassell, G. and Singer, R. H. (1997) mRNA and cytoskeletal filaments. Curr. Opin. Cell. Biol. 9, 109–115.PubMedCrossRefGoogle Scholar
  27. 27.
    Bloch, K. D. (1999) Regulation of endothelial NO synthase mRNA stability: RNA-binding proteins crowd on the 3′-untranslated region. Circ. Res. 85, 653–655.PubMedGoogle Scholar
  28. 28.
    Lai, P. F., Mohamed, F., Monge, J. C., and Stewart, D. J. (2003) Downregulation of eNOS mRNA expression by TNFalpha: identification and functional characterization of RNA-protein interactions in the 3′UTR. Cardiovasc. Res. 59, 160–168.PubMedCrossRefGoogle Scholar
  29. 29.
    Searles, C. D., Ide, L., Davis, M. E., and Harrison, D. G. (2002) Post-transcriptional regulation of endothelial nitric oxide synthase during cell growth: evidence for the role of actin. FASEB J. 16, A440.Google Scholar
  30. 30.
    Venema, V. J., Marrero, M. B., and Venema, R. C. (1996) Bradykinin-stimulated protein tyrosine phosphorylation promotes endothelial nitric oxide synthase translocation to the cytoskeleton. Biochem. Biophys. Res. Commun. 226, 703–710.PubMedCrossRefGoogle Scholar
  31. 31.
    Su, Y., Zharikov, S. I., and Block, E. R. (2002) Microtubule-active agents modify nitric oxide production in pulmonary artery endothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 282, L1183-L1189.PubMedGoogle Scholar
  32. 32.
    Lee, N. P. and Yan, C. C. (2003) Regulation of Sertoli cell tight junction dynamics in the rat testis via the nitric oxide synthase/soluble guanylate cyclase/3′,5′-cyclic guanosine monophosphate/protein kinase G signaling pathway: an in vitro study. Endocrinology 144, 3114–3129.PubMedCrossRefGoogle Scholar
  33. 33.
    Kondrikov, D., Su, Y., Han, H.-R., and Block, E. R. (2004) Direct interaction of endothelial nitric oxide synthase with the actin cytoskeleton. FASEB J. 15, A1026.Google Scholar
  34. 34.
    Kanzaki, M. and Pessin, J. E. (2002) Caveolin-associated filamentous actin (Cav-actin) defines a novel F-actin structure in adipocytes. J. Biol. Chem. 277, 25867–25869.PubMedCrossRefGoogle Scholar
  35. 35.
    Nishida, E., Koyasu, S., Sakai, H., and Yahara, I. (1986) Calmodulin-regulated binding of the 90-kDa heat shock protein to actin filaments. J. Biol. Chem. 261, 16033–16036.PubMedGoogle Scholar
  36. 36.
    Koyasu, S., Nishida, E., Kadowaki, T., Matsuzaki, F., Iida, K., Harada, F., Kasuga, M., Sakai, H., and Yahara, I. (1986) Two mammalian heat shock proteins, HSP90 and HSP100, are actin-binding proteins. Proc. Natl. Acad. Sci. U S A 83, 8054–8058.PubMedCrossRefGoogle Scholar
  37. 37.
    Czar, M. J., Welsh, M. J., and Pratt, W. B. (1996) Immunofluorescence localization of the 90-kDa heat-shock protein to cytoskeleton. Eur. J. Cell Biol. 70, 322–330.PubMedGoogle Scholar
  38. 38.
    Orth, J. D. and McNiven, M. A. (2003) Dynamin at the actin-membrane interface. Curr. Opin. Cell. Biol. 15, 31–39.PubMedCrossRefGoogle Scholar
  39. 39.
    Zharikov, S. I. and Block, E. R. (2000) Association of L-arginine transporters with fodrin: implications for hypoxic inhibition of arginine uptake. Am. J. Physiol. Lung Cell Mol. Physiol. 278, L111-L117.PubMedGoogle Scholar
  40. 40.
    Zimmermann, K., Opitz, N., Dedio, J., Renne, C., Muller-Esterl, W., and Oess, S. (2002) NOSTRIN: a protein modulating nitric oxide release and subcellular distribution of endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U S A 99, 17167–17172.PubMedCrossRefGoogle Scholar
  41. 41.
    McDonald, K. K., Zharikov, S., Block, E. R., and Kilberg, M. S. (1997) A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the “arginine paradox”. J. Biol. Chem. 272, 31213–31216.PubMedCrossRefGoogle Scholar
  42. 42.
    Dedio, J., Konig, P., Wohlfart, P., Schroeder, C., Kummer, W., and Muller-Esterl, W. (2001) NOSIP, a novel modulator of endothelial nitric oxide synthase activity. FASEB J. 15, 79–89.PubMedCrossRefGoogle Scholar
  43. 43.
    Whitney, J. A., German, Z., Sherman, T. S., Yuhanna, I. S., and Shaul, P. W. (2000) Cell growth modulates nitric oxide synthase expression in fetal pulmonary artery endothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 278, L131-L138.PubMedGoogle Scholar
  44. 44.
    Laufs, U., Endres, M., Custodis, F., Gertz, K., Nickenig, G., Liao, J. K., and Bohm M. (2000) Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation 102, 3104–3110.PubMedGoogle Scholar
  45. 45.
    Witteck, A., Yao, Y., Fechir, M., Forstermann, U., and Kleinert, H. (2003) Rho protein-mediated changes in the structure of the actin cytoskeleton regulate human inducible NO synthase gene expression. Exp. Cell Res. 287, 106–115.PubMedCrossRefGoogle Scholar
  46. 46.
    Zeng, C. and Morrison, A. R. (2001) Disruption of the actin cytoskeleton regulates cytokine-induced iNOS expression. Am. J. Physiol. Cell Physiol. 281, C932-C940.PubMedGoogle Scholar
  47. 47.
    Hattori, Y. and Kasai, K. (2004) Disruption of the actin cytoskeleton up-regulates iNOS expression in vascular smooth muscle cells. J. Cardiovasc. Pharmacol. 43, 209–213.PubMedCrossRefGoogle Scholar
  48. 48.
    Marczin, N., Jilling, T., Papapetropoulos, A., Go, C., and Catravas, J. D. (1996) Cytoskeleton-dependent activation of the inducible nitric oxide synthase in cultured aortic smooth muscle cells. Br. J. Pharmacol. 118, 1085–1094.PubMedGoogle Scholar
  49. 49.
    Sotiropoulos, A., Gineitis, D., Copeland, J., and Treisman, R. (1999) Signal-regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98, 159–169.PubMedCrossRefGoogle Scholar
  50. 50.
    Marczin, N., Papapetropoulos, A., Jilling, T., and Catravas, J. D. (1993) Prevention of nitric oxide synthase induction in vascular smooth muscle cells by microtubule depolymerizing agents. Br. J. Pharmacol. 109, 603–605.PubMedGoogle Scholar
  51. 51.
    Kirikae, T., Kirikae, F., Oghiso, Y., and Nakano, M. (1996) Microtubule-disrupting agents inhibit nitric oxide production in murine peritoneal macrophages stimulated with lipopolysaccharide or paclitaxel (Taxol). Infect. Immun. 64, 3379–3384.PubMedGoogle Scholar
  52. 52.
    Vanhatalo, S., Lumme, A., and Soinila, S. (1998) Colchicine differentially induces the expressions of nitric oxide synthases in central and peripheral catecholaminergic neurons. Exp. Neurol. 150, 107–114.PubMedCrossRefGoogle Scholar
  53. 53.
    Ory, S., Destaing, O., and Jurdic, P. (2002) Microtubule dynamics differentially regulates Rho and Rac activity and triggers Rho-independent stress fiber formation in macrophage polykaryons. Eur. J. Cell Biol. 81, 351–362.PubMedCrossRefGoogle Scholar
  54. 54.
    Jung, H. I., Shin, I., Park, Y. M., Kang, K. W., and Ha, K. S. (1997) Colchicine activates actin polymerization by microtubule depolymerization. Mol. Cells 7, 431–437.PubMedGoogle Scholar
  55. 55.
    Kajstura, J., Sowa, G., and Wronska, D. (1993) Induction of DNA synthesis by microtubule depolymerization is mediated by actin filaments. Cytobios 76, 67–74.PubMedGoogle Scholar
  56. 56.
    Taylor, L. S., Cox, G. W., Melillo, G., Bosco, M. C., and Espinoza-Delgado, I. (1997) Bryostatin-1 and IFN-gamma synergize for the expression of the inducible nitric oxide synthase gene and for nitric oxide production in murine macrophages. Cancer Res. 57, 2468–2473.PubMedGoogle Scholar
  57. 57.
    Weisz, A., Oguchi, S., Cicatiello, L., and Esumi, H. (1994) Dual mechanism for the control of inducible-type NO synthase gene expression in macrophages during activation by interferongamma and bacterial lipopolysaccharide. Transcriptional and post-transcriptional regulation. J. Biol. Chem. 269, 8324–8333.PubMedGoogle Scholar
  58. 58.
    Soderberg, M., Raffalli-Mathieu, F., and Lang, M. A. (2002) Inflammation modulates the interaction of heterogeneous nuclear ribonucleoprotein (hnRNP) I/polypyrimidine tract binding protein and hnRNP L with the 3′ untranslated region of the murine inducible nitric-oxide synthase mRNA. Mol. Pharmacol. 62, 423–431.PubMedCrossRefGoogle Scholar
  59. 59.
    Rodriguez-Pascual, F., Hausding, M., Ihrig-Biedert, I., Furneaux, H., Levy, A. P., Forstermann, U., and Kleinert, H. (2000) Complex contribution of the 3′-untranslated region to the expressional regulation of the human inducible nitric-oxide synthase gene. Involvement of the RNA-binding protein HuR. J. Biol. Chem. 275, 26040–26049.PubMedCrossRefGoogle Scholar
  60. 60.
    Webb, J. L., Harvey, M. W., Holden, D. W., and Evans, T. J. (2001) Macrophage nitric oxide synthase associates with cortical actin but is not recruited to phagosomes. Infect. Immun. 69, 6391–6400.PubMedCrossRefGoogle Scholar
  61. 61.
    Daniliuc, S., Bitterman, H., Rahat, M. A., Kinarty, A., Rosenzweig, D., Lahat, N., and Nitza, L. (2003) Hypoxia inactivates inducible nitric oxide synthase in mouse macrophages by disrupting its interaction with alpha-actinin 4. J. Immunol. 171, 3225–3232.PubMedGoogle Scholar
  62. 62.
    Yoshida, M. and Xia, Y. (2003) Heat shock protein 90 as an endogenous protein enhancer of inducible nitric-oxide synthase. J. Biol. Chem. 278, 36953–36958.PubMedCrossRefGoogle Scholar
  63. 63.
    Gorodeski, G. I. (2000) NO increases permeability of cultured human cervical epithelia by cGMP-mediated increase in G-actin. Am. J. Physiol. Cell Physiol. 278, C942-C952.PubMedGoogle Scholar
  64. 64.
    Zhang, J. S., Kraus, W. E., and Truskey, G. A. (2004) Stretch-induced nitric oxide modulates mechanical properties of skeletal muscle cells. Am. J. Physiol. Cell Physiol. 287, C292-C299.PubMedCrossRefGoogle Scholar
  65. 65.
    Tidball, J. G., Lavergne, E., Lau, K. S., Spencer, M. J., Stull, J. T. and Wehling, M. (1998) Mechanical loading regulates NOS expression and activity in developing and adult skeletal muscle. Am. J. Physiol. 275, C260-C266.PubMedGoogle Scholar
  66. 66.
    Saur, D., Neuhuber, W. L., Gengenbach, B., Huber, A., Schusdziarra, V., and Allescher, H. D. (2002) Site-specific gene expression of nNOS variants in distinct functional regions of rat gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G349-G358.PubMedGoogle Scholar
  67. 67.
    Boissel, J. P., Zelenka, M., Godtel-Armbrust, U., Feuerstein, T. J., and Ulrich, F. (2003) Transcription of different exons 1 of the human neuronal nitric oxide synthase gene is dynamically regulated in a cell- and stimulus-specific manner. Biol. Chem. 384, 351–362.PubMedCrossRefGoogle Scholar
  68. 68.
    Ort, T., Maksimova, E., Dirkx, R., Kachinsky, A. M., Berghs, S., Froehner, S. C., and Solimena, M. (2000) The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of beta2-syntrophin and nNOS in pancreatic beta-cells. Eur. J. Cell Biol. 79, 621–630.PubMedCrossRefGoogle Scholar
  69. 69.
    Brenman, J. E., Chao, D. S., Gee, S. H., McGee, A. W., Craven, S. E., Santillano, D. R., Wu, Z., Huang, F., Xia, H., Peters, M. F., Froehner, S. C., and Bredt, D. S. (1996) Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 84, 757–767.PubMedCrossRefGoogle Scholar
  70. 70.
    Hillier, B. J., Christopherson, K. S., Prehoda, K. E., Bredt, D. S., and Lim, W. A. (1999) Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex. Science 284, 812–815.PubMedCrossRefGoogle Scholar
  71. 71.
    Peters, M. F., Adams, M. E. and Froehner S. C. (1997) Differential association of syntrophin pairs with the dystrophin complex. J. Cell. Biol. 138, 81–93.PubMedCrossRefGoogle Scholar
  72. 72.
    Marechal, G., and Gailly, P. (1999) Effects of nitric oxide on the contraction of skeletal muscle. Cell Mol. Life Sci. 55, 1088–1102.PubMedCrossRefGoogle Scholar
  73. 73.
    Reid, M. B. (1998) Role of nitric oxide in skeletal muscle: synthesis, distribution and functional importance. Acta Physiol. Scand. 162, 401–409.PubMedCrossRefGoogle Scholar
  74. 74.
    Koh, T. J. and Tidball, J. G. (2000) Nitric oxide inhibits calpain-mediated proteolysis of talin in skeletal muscle cells. Am. J. Physiol. Cell Physiol. 279, C806-C812.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Yunchao Su
    • 1
  • Dmitry Kondrikov
    • 1
  • Edward R. Block
    • 1
    • 2
  1. 1.Department of MedicineUniversity of FloridaGainesville
  2. 2.Research ServiceMalcolm Randall Veterans Affairs Medical CenterGainesville

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