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. 1994 Dec;113(4):1448–1454. doi: 10.1111/j.1476-5381.1994.tb17159.x

Inhibition of nitric oxide synthesis in vascular smooth muscle by retinoids.

K Hirokawa 1, K M O'Shaughnessy 1, P Ramrakha 1, M R Wilkins 1
PMCID: PMC1510519  PMID: 7534188

Abstract

1. These studies examine the effect of retinoids on interleukin 1 beta (IL-1 beta)-induced nitric oxide synthase (NOS) activity in cultured rat aortic vascular smooth muscle (VSM) cells and isolated rat aortic rings. 2. All-trans-retinoic acid (all-trans-RA, 0.1-10 microM) and its active analogues produced concentration-dependent inhibition of IL-1 beta (0.1-10 ng ml-1)-induced nitrite production in cultured VSM cells. In contrast, the inactive retinoid, Ro 14-6113 (0.1-10 microM), had no effect on IL-1 beta-induced nitrite production. 3. Since some of the actions of retinoids are mediated by induction of transforming growth factor beta (TGF-beta), its effect on inducible NOS activity in VSM cells was examined. TGF-beta produced concentration-dependent (0.1-10 ng ml-1) inhibition of IL-1 beta-induced nitrite production and the maximum effect (approximately 90% inhibition) was significantly greater than that seen with all-trans-RA (approximately 70% with 10 microM). However, an anti-TGF-beta antibody (50 micrograms ml-1) which blocked the effect of exogenous TGF-beta (5 ng ml-1) did not significantly reverse the inhibitory action of all-trans-RA (10 microM). 4. In addition to inhibiting IL-1 beta-induced nitrite production, all-trans-RA (10 microM) reduced substantially inducible NOS mRNA and protein levels in IL-1 beta-induced VSM cells (P < 0.01). 5. Incubation of isolated rat aortic rings with IL-1 beta (10 ng ml-1) caused a progressive resistance of the rings to the vasoconstrictor action of phenylephrine (10 nM to 10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beasley D., Schwartz J. H., Brenner B. M. Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest. 1991 Feb;87(2):602–608. doi: 10.1172/JCI115036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blomhoff R., Green M. H., Green J. B., Berg T., Norum K. R. Vitamin A metabolism: new perspectives on absorption, transport, and storage. Physiol Rev. 1991 Oct;71(4):951–990. doi: 10.1152/physrev.1991.71.4.951. [DOI] [PubMed] [Google Scholar]
  3. Breitman T. R., Selonick S. E., Collins S. J. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A. 1980 May;77(5):2936–2940. doi: 10.1073/pnas.77.5.2936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brinckerhoff C. E., Plucinska I. M., Sheldon L. A., O'Connor G. T. Half-life of synovial cell collagenase mRNA is modulated by phorbol myristate acetate but not by all-trans-retinoic acid or dexamethasone. Biochemistry. 1986 Oct 21;25(21):6378–6384. doi: 10.1021/bi00369a006. [DOI] [PubMed] [Google Scholar]
  5. Brown L. A., Nunez D. J., Wilkins M. R. Differential regulation of natriuretic peptide receptor messenger RNAs during the development of cardiac hypertrophy in the rat. J Clin Invest. 1993 Dec;92(6):2702–2712. doi: 10.1172/JCI116887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Chytil F., Riaz-ul-Haq Vitamin A mediated gene expression. Crit Rev Eukaryot Gene Expr. 1990;1(1):61–73. [PubMed] [Google Scholar]
  8. Cunha F. Q., Moncada S., Liew F. Y. Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-gamma in murine macrophages. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1155–1159. doi: 10.1016/0006-291x(92)91852-h. [DOI] [PubMed] [Google Scholar]
  9. Heyman R. A., Mangelsdorf D. J., Dyck J. A., Stein R. B., Eichele G., Evans R. M., Thaller C. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992 Jan 24;68(2):397–406. doi: 10.1016/0092-8674(92)90479-v. [DOI] [PubMed] [Google Scholar]
  10. Ignarro L. J., Fukuto J. M., Griscavage J. M., Rogers N. E., Byrns R. E. Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8103–8107. doi: 10.1073/pnas.90.17.8103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ishii H., Horie S., Kizaki K., Kazama M. Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumor necrosis factor. Blood. 1992 Nov 15;80(10):2556–2562. [PubMed] [Google Scholar]
  12. Kirschenlohr H. L., Metcalfe J. C., Weissberg P. L., Grainger D. J. Adult human aortic smooth muscle cells in culture produce active TGF-beta. Am J Physiol. 1993 Aug;265(2 Pt 1):C571–C576. doi: 10.1152/ajpcell.1993.265.2.C571. [DOI] [PubMed] [Google Scholar]
  13. Levin A. A., Sturzenbecker L. J., Kazmer S., Bosakowski T., Huselton C., Allenby G., Speck J., Kratzeisen C., Rosenberger M., Lovey A. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992 Jan 23;355(6358):359–361. doi: 10.1038/355359a0. [DOI] [PubMed] [Google Scholar]
  14. Lohnes D., Dierich A., Ghyselinck N., Kastner P., Lampron C., LeMeur M., Lufkin T., Mendelsohn C., Nakshatri H., Chambon P. Retinoid receptors and binding proteins. J Cell Sci Suppl. 1992;16:69–76. doi: 10.1242/jcs.1992.supplement_16.9. [DOI] [PubMed] [Google Scholar]
  15. Mehta K., McQueen T., Tucker S., Pandita R., Aggarwal B. B. Inhibition by all-trans-retinoic acid of tumor necrosis factor and nitric oxide production by peritoneal macrophages. J Leukoc Biol. 1994 Mar;55(3):336–342. doi: 10.1002/jlb.55.3.336. [DOI] [PubMed] [Google Scholar]
  16. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  17. Mühl H., Kunz D., Rob P., Pfeilschifter J. Cyclosporin derivatives inhibit interleukin 1 beta induction of nitric oxide synthase in renal mesangial cells. Eur J Pharmacol. 1993 Nov 2;249(1):95–100. doi: 10.1016/0014-2999(93)90666-6. [DOI] [PubMed] [Google Scholar]
  18. Nicholson R. C., Mader S., Nagpal S., Leid M., Rochette-Egly C., Chambon P. Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO J. 1990 Dec;9(13):4443–4454. doi: 10.1002/j.1460-2075.1990.tb07895.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nunokawa Y., Ishida N., Tanaka S. Cloning of inducible nitric oxide synthase in rat vascular smooth muscle cells. Biochem Biophys Res Commun. 1993 Feb 26;191(1):89–94. doi: 10.1006/bbrc.1993.1188. [DOI] [PubMed] [Google Scholar]
  20. Ochoa J. B., Curti B., Peitzman A. B., Simmons R. L., Billiar T. R., Hoffman R., Rault R., Longo D. L., Urba W. J., Ochoa A. C. Increased circulating nitrogen oxides after human tumor immunotherapy: correlation with toxic hemodynamic changes. J Natl Cancer Inst. 1992 Jun 3;84(11):864–867. doi: 10.1093/jnci/84.11.864. [DOI] [PubMed] [Google Scholar]
  21. Orfanos C. E., Bauer R. Evidence for anti-inflammatory activities of oral synthetic retinoids: experimental findings and clinical experience. Br J Dermatol. 1983 Jul;109 (Suppl 25):55–60. [PubMed] [Google Scholar]
  22. Parsaee H., McEwan J. R., Joseph S., MacDermot J. Differential sensitivities of the prostacyclin and nitric oxide biosynthetic pathways to cytosolic calcium in bovine aortic endothelial cells. Br J Pharmacol. 1992 Dec;107(4):1013–1019. doi: 10.1111/j.1476-5381.1992.tb13400.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Radomski M. W., Palmer R. M., Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci U S A. 1990 Dec;87(24):10043–10047. doi: 10.1073/pnas.87.24.10043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rees D. D., Palmer R. M., Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989 May;86(9):3375–3378. doi: 10.1073/pnas.86.9.3375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Riveros-Moreno V., Beddell C., Moncada S. Nitric oxide synthase. Structural studies using anti-peptide antibodies. Eur J Biochem. 1993 Aug 1;215(3):801–808. doi: 10.1111/j.1432-1033.1993.tb18095.x. [DOI] [PubMed] [Google Scholar]
  26. Roberts A. B., Sporn M. B. Mechanistic interrelationships between two superfamilies: the steroid/retinoid receptors and transforming growth factor-beta. Cancer Surv. 1992;14:205–220. [PubMed] [Google Scholar]
  27. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schini V. B., Catovsky S., Durante W., Scott-Burden T., Schafer A. I., Vanhoutte P. M. Thrombin inhibits induction of nitric oxide synthase in vascular smooth muscle cells. Am J Physiol. 1993 Feb;264(2 Pt 2):H611–H616. doi: 10.1152/ajpheart.1993.264.2.H611. [DOI] [PubMed] [Google Scholar]
  29. Schini V. B., Durante W., Elizondo E., Scott-Burden T., Junquero D. C., Schafer A. I., Vanhoutte P. M. The induction of nitric oxide synthase activity is inhibited by TGF-beta 1, PDGFAB and PDGFBB in vascular smooth muscle cells. Eur J Pharmacol. 1992 Jun 17;216(3):379–383. doi: 10.1016/0014-2999(92)90434-6. [DOI] [PubMed] [Google Scholar]
  30. Schüle R., Rangarajan P., Yang N., Kliewer S., Ransone L. J., Bolado J., Verma I. M., Evans R. M. Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6092–6096. doi: 10.1073/pnas.88.14.6092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Scott-Burden T., Schini V. B., Elizondo E., Junquero D. C., Vanhoutte P. M. Platelet-derived growth factor suppresses and fibroblast growth factor enhances cytokine-induced production of nitric oxide by cultured smooth muscle cells. Effects on cell proliferation. Circ Res. 1992 Nov;71(5):1088–1100. doi: 10.1161/01.res.71.5.1088. [DOI] [PubMed] [Google Scholar]
  32. Slotman G. J., Fisher C. J., Jr, Bone R. C., Clemmer T. P., Metz C. A. Detrimental effects of high-dose methylprednisolone sodium succinate on serum concentrations of hepatic and renal function indicators in severe sepsis and septic shock. The Methylprednisolone Severe Sepsis Study Group. Crit Care Med. 1993 Feb;21(2):191–195. doi: 10.1097/00003246-199302000-00008. [DOI] [PubMed] [Google Scholar]
  33. Vahlquist A. Long-term safety of retinoid therapy. J Am Acad Dermatol. 1992 Dec;27(6 Pt 2):S29–S33. doi: 10.1016/s0190-9622(08)80257-5. [DOI] [PubMed] [Google Scholar]
  34. Wan Y. J., Wang L., Wu T. C. Detection of retinoic acid receptor mRNA in rat tissues by reverse transcriptase-polymerase chain reaction. J Mol Endocrinol. 1992 Dec;9(3):291–294. doi: 10.1677/jme.0.0090291. [DOI] [PubMed] [Google Scholar]
  35. Wang C., Kelly J., Bowen-Pope D. F., Stiles C. D. Retinoic acid promotes transcription of the platelet-derived growth factor alpha-receptor gene. Mol Cell Biol. 1990 Dec;10(12):6781–6784. doi: 10.1128/mcb.10.12.6781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Warrell R. P., Jr, de Thé H., Wang Z. Y., Degos L. Acute promyelocytic leukemia. N Engl J Med. 1993 Jul 15;329(3):177–189. doi: 10.1056/NEJM199307153290307. [DOI] [PubMed] [Google Scholar]
  37. Xie Q. W., Whisnant R., Nathan C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med. 1993 Jun 1;177(6):1779–1784. doi: 10.1084/jem.177.6.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zembowicz A., Vane J. R. Induction of nitric oxide synthase activity by toxic shock syndrome toxin 1 in a macrophage-monocyte cell line. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2051–2055. doi: 10.1073/pnas.89.6.2051. [DOI] [PMC free article] [PubMed] [Google Scholar]

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