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. 1997 Oct;151(4):919–925.

Inducible nitric oxide synthase expression in coronary arteries of transplanted human hearts with accelerated graft arteriosclerosis.

A Lafond-Walker 1, C L Chen 1, S Augustine 1, T C Wu 1, R H Hruban 1, C J Lowenstein 1
PMCID: PMC1858042  PMID: 9327724

Abstract

Inducible nitric oxide synthase (iNOS) is a high-output isoform of NOS that produces nitric oxide (NO), a nonspecific immune effector molecule. In some animal models of autoimmunity, the induction of iNOS has been shown to lead to inflammation and tissue damage, and it has been suggested that iNOS is an immune mediator in humans as well. Using in situ hybridization and immunohistochemical techniques, we demonstrate that iNOS mRNA and protein are present in the coronary arteries of transplanted human hearts with accelerated graft arteriosclerosis (AGA). iNOS is expressed in cells morphologically consistent with macrophages in the neointima of 7 of 10 of the transplanted vessels with AGA that were examined. In serial sections, these same cells express the macrophage marker CD68. In contrast, iNOS is absent from five native coronary arteries with atherosclerosis and absent from two normal coronary arteries. Although iNOS is expressed in macrophages in AGA, its role in the pathogenesis of AGA is unknown.

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Selected References

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

  1. Akyürek L. M., Fellström B. C., Yan Z. Q., Hansson G. K., Funa K., Larsson E. Inducible and endothelial nitric oxide synthase expression during development of transplant arteriosclerosis in rat aortic grafts. Am J Pathol. 1996 Dec;149(6):1981–1990. [PMC free article] [PubMed] [Google Scholar]
  2. Albina J. E., Cui S., Mateo R. B., Reichner J. S. Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol. 1993 Jun 1;150(11):5080–5085. [PubMed] [Google Scholar]
  3. Balligand J. L., Ungureanu-Longrois D., Simmons W. W., Pimental D., Malinski T. A., Kapturczak M., Taha Z., Lowenstein C. J., Davidoff A. J., Kelly R. A. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem. 1994 Nov 4;269(44):27580–27588. [PubMed] [Google Scholar]
  4. Balligand J. L., Ungureanu D., Kelly R. A., Kobzik L., Pimental D., Michel T., Smith T. W. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest. 1993 May;91(5):2314–2319. doi: 10.1172/JCI116461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Benvenuti C., Bories P. N., Loisance D. Increased serum nitrate concentration in cardiac transplant patients. A marker for acute allograft cellular rejection. Transplantation. 1996 Mar 15;61(5):745–749. doi: 10.1097/00007890-199603150-00013. [DOI] [PubMed] [Google Scholar]
  6. Billiar T. R. Nitric oxide. Novel biology with clinical relevance. Ann Surg. 1995 Apr;221(4):339–349. doi: 10.1097/00000658-199504000-00003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bredt D. S., Hwang P. M., Glatt C. E., Lowenstein C., Reed R. R., Snyder S. H. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature. 1991 Jun 27;351(6329):714–718. doi: 10.1038/351714a0. [DOI] [PubMed] [Google Scholar]
  8. Burkart V., Imai Y., Kallmann B., Kolb H. Cyclosporin A protects pancreatic islet cells from nitric oxide-dependent macrophage cytotoxicity. FEBS Lett. 1992 Nov 16;313(1):56–58. doi: 10.1016/0014-5793(92)81183-m. [DOI] [PubMed] [Google Scholar]
  9. Day J. D., Rayburn B. K., Gaudin P. B., Baldwin W. M., 3rd, Lowenstein C. J., Kasper E. K., Baughman K. L., Baumgartner W. A., Hutchins G. M., Hruban R. H. Cardiac allograft vasculopathy: the central pathogenetic role of ischemia-induced endothelial cell injury. J Heart Lung Transplant. 1995 Nov-Dec;14(6 Pt 2):S142–S149. [PubMed] [Google Scholar]
  10. Fast D. J., Lynch R. C., Leu R. W. Cyclosporin A inhibits nitric oxide production by L929 cells in response to tumor necrosis factor and interferon-gamma. J Interferon Res. 1993 Jun;13(3):235–240. doi: 10.1089/jir.1993.13.235. [DOI] [PubMed] [Google Scholar]
  11. Finkel M. S., Oddis C. V., Jacob T. D., Watkins S. C., Hattler B. G., Simmons R. L. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992 Jul 17;257(5068):387–389. doi: 10.1126/science.1631560. [DOI] [PubMed] [Google Scholar]
  12. Gaudin P. B., Rayburn B. K., Hutchins G. M., Kasper E. K., Baughman K. L., Goodman S. N., Lecks L. E., Baumgartner W. A., Hruban R. H. Peritransplant injury to the myocardium associated with the development of accelerated arteriosclerosis in heart transplant recipients. Am J Surg Pathol. 1994 Apr;18(4):338–346. doi: 10.1097/00000478-199404000-00002. [DOI] [PubMed] [Google Scholar]
  13. Geller D. A., Lowenstein C. J., Shapiro R. A., Nussler A. K., Di Silvio M., Wang S. C., Nakayama D. K., Simmons R. L., Snyder S. H., Billiar T. R. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3491–3495. doi: 10.1073/pnas.90.8.3491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harbrecht B. G., Billiar T. R. The role of nitric oxide in Kupffer cell-hepatocyte interactions. Shock. 1995 Feb;3(2):79–87. [PubMed] [Google Scholar]
  15. Hruban R. H., Beschorner W. E., Baumgartner W. A., Augustine S. M., Ren H., Reitz B. A., Hutchins G. M. Accelerated arteriosclerosis in heart transplant recipients is associated with a T-lymphocyte-mediated endothelialitis. Am J Pathol. 1990 Oct;137(4):871–882. [PMC free article] [PubMed] [Google Scholar]
  16. Ignarro L. J. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol. 1990;30:535–560. doi: 10.1146/annurev.pa.30.040190.002535. [DOI] [PubMed] [Google Scholar]
  17. Janssens S. P., Shimouchi A., Quertermous T., Bloch D. B., Bloch K. D. Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem. 1992 Jul 25;267(21):14519–14522. [PubMed] [Google Scholar]
  18. Lamas S., Marsden P. A., Li G. K., Tempst P., Michel T. Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6348–6352. doi: 10.1073/pnas.89.14.6348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lancaster J. R., Jr, Langrehr J. M., Bergonia H. A., Murase N., Simmons R. L., Hoffman R. A. EPR detection of heme and nonheme iron-containing protein nitrosylation by nitric oxide during rejection of rat heart allograft. J Biol Chem. 1992 Jun 5;267(16):10994–10998. [PubMed] [Google Scholar]
  20. Levy M. M., Ketchum R. J., Perloff J. R., Park D. H., Brayman K. L. Cyclosporin A inhibits nitric oxide production in an in vitro xenogeneic islet/splenocyte co-culture system. Transplant Proc. 1994 Oct;26(5):2886–2887. [PubMed] [Google Scholar]
  21. Lewis N. P., Tsao P. S., Rickenbacher P. R., Xue C., Johns R. A., Haywood G. A., von der Leyen H., Trindade P. T., Cooke J. P., Hunt S. A. Induction of nitric oxide synthase in the human cardiac allograft is associated with contractile dysfunction of the left ventricle. Circulation. 1996 Feb 15;93(4):720–729. doi: 10.1161/01.cir.93.4.720. [DOI] [PubMed] [Google Scholar]
  22. Libby P., Tanaka H. The pathogenesis of coronary arteriosclerosis ("chronic rejection") in transplanted hearts. Clin Transplant. 1994 Jun;8(3 Pt 2):313–318. [PubMed] [Google Scholar]
  23. Lowenstein C. J., Glatt C. S., Bredt D. S., Snyder S. H. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6711–6715. doi: 10.1073/pnas.89.15.6711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lowenstein C. J., Snyder S. H. Nitric oxide, a novel biologic messenger. Cell. 1992 Sep 4;70(5):705–707. doi: 10.1016/0092-8674(92)90301-r. [DOI] [PubMed] [Google Scholar]
  25. Lyons C. R., Orloff G. J., Cunningham J. M. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem. 1992 Mar 25;267(9):6370–6374. [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  29. Park J. S., Rader J. S., Wu T. C., Laimins L. A., Currie J. L., Kurman R. J., Shah K. V. HPV-16 viral transcripts in vulvar neoplasia: preliminary studies. Gynecol Oncol. 1991 Sep;42(3):250–255. doi: 10.1016/0090-8258(91)90354-8. [DOI] [PubMed] [Google Scholar]
  30. Paul L. C., Myllärniemi M., Muzaffar S., Benediktsson H. Nitric oxide synthase inhibition is associated with decreased survival of cardiac allografts in the rat. Transplantation. 1996 Oct 27;62(8):1193–1195. doi: 10.1097/00007890-199610270-00032. [DOI] [PubMed] [Google Scholar]
  31. Rice W. G., Hillyer C. D., Harten B., Schaeffer C. A., Dorminy M., Lackey D. A., 3rd, Kirsten E., Mendeleyev J., Buki K. G., Hakam A. Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7703–7707. doi: 10.1073/pnas.89.16.7703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Roberts A. B., Vodovotz Y., Roche N. S., Sporn M. B., Nathan C. F. Role of nitric oxide in antagonistic effects of transforming growth factor-beta and interleukin-1 beta on the beating rate of cultured cardiac myocytes. Mol Endocrinol. 1992 Nov;6(11):1921–1930. doi: 10.1210/mend.6.11.1282674. [DOI] [PubMed] [Google Scholar]
  33. Russell M. E., Wallace A. F., Wyner L. R., Newell J. B., Karnovsky M. J. Upregulation and modulation of inducible nitric oxide synthase in rat cardiac allografts with chronic rejection and transplant arteriosclerosis. Circulation. 1995 Aug 1;92(3):457–464. doi: 10.1161/01.cir.92.3.457. [DOI] [PubMed] [Google Scholar]
  34. Salomon R. N., Hughes C. C., Schoen F. J., Payne D. D., Pober J. S., Libby P. Human coronary transplantation-associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft endothelial cells. Am J Pathol. 1991 Apr;138(4):791–798. [PMC free article] [PubMed] [Google Scholar]
  35. Sarih M., Souvannavong V., Adam A. Nitric oxide synthase induces macrophage death by apoptosis. Biochem Biophys Res Commun. 1993 Mar 15;191(2):503–508. doi: 10.1006/bbrc.1993.1246. [DOI] [PubMed] [Google Scholar]
  36. Sarkar R., Meinberg E. G., Stanley J. C., Gordon D., Webb R. C. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res. 1996 Feb;78(2):225–230. doi: 10.1161/01.res.78.2.225. [DOI] [PubMed] [Google Scholar]
  37. Sessa W. C., Harrison J. K., Barber C. M., Zeng D., Durieux M. E., D'Angelo D. D., Lynch K. R., Peach M. J. Molecular cloning and expression of a cDNA encoding endothelial cell nitric oxide synthase. J Biol Chem. 1992 Aug 5;267(22):15274–15276. [PubMed] [Google Scholar]
  38. Shi C., Lee W. S., He Q., Zhang D., Fletcher D. L., Jr, Newell J. B., Haber E. Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4051–4056. doi: 10.1073/pnas.93.9.4051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Shindo T., Ikeda U., Ohkawa F., Takahashi M., Funayama H., Nishinaga M., Kawahara Y., Yokoyama M., Kasahara T., Shimada K. Nitric oxide synthesis in rat cardiac myocytes and fibroblasts. Life Sci. 1994;55(14):1101–1108. doi: 10.1016/0024-3205(94)00238-x. [DOI] [PubMed] [Google Scholar]
  40. Singh K., Balligand J. L., Fischer T. A., Smith T. W., Kelly R. A. Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. J Biol Chem. 1996 Jan 12;271(2):1111–1117. doi: 10.1074/jbc.271.2.1111. [DOI] [PubMed] [Google Scholar]
  41. Stamler J. S. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell. 1994 Sep 23;78(6):931–936. doi: 10.1016/0092-8674(94)90269-0. [DOI] [PubMed] [Google Scholar]
  42. Ungureanu-Longrois D., Balligand J. L., Simmons W. W., Okada I., Kobzik L., Lowenstein C. J., Kunkel S. L., Michel T., Kelly R. A., Smith T. W. Induction of nitric oxide synthase activity by cytokines in ventricular myocytes is necessary but not sufficient to decrease contractile responsiveness to beta-adrenergic agonists. Circ Res. 1995 Sep;77(3):494–502. doi: 10.1161/01.res.77.3.494. [DOI] [PubMed] [Google Scholar]
  43. Winlaw D. S., Schyvens C. G., Smythe G. A., Du Z. Y., Rainer S. P., Lord R. S., Spratt P. M., Macdonald P. S. Selective inhibition of nitric oxide production during cardiac allograft rejection causes a small increase in graft survival. Transplantation. 1995 Jul 15;60(1):77–82. doi: 10.1097/00007890-199507150-00015. [DOI] [PubMed] [Google Scholar]
  44. Worrall N. K., Chang K., Suau G. M., Allison W. S., Misko T. P., Sullivan P. M., Tilton R. G., Williamson J. R., Ferguson T. B., Jr Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection. Circ Res. 1996 May;78(5):769–779. doi: 10.1161/01.res.78.5.769. [DOI] [PubMed] [Google Scholar]
  45. Worrall N. K., Misko T. P., Sullivan P. M., Hui J. J., Ferguson T. B., Jr Inhibition of inducible nitric oxide synthase attenuates established acute cardiac allograft rejection. Ann Thorac Surg. 1996 Aug;62(2):378–385. [PubMed] [Google Scholar]
  46. Worrall N. K., Misko T. P., Sullivan P. M., Hui J. J., Rodi C. P., Ferguson T. B., Jr Corticosteroids inhibit expression of inducible nitric oxide synthase during acute cardiac allograft rejection. Transplantation. 1996 Jan 27;61(2):324–328. doi: 10.1097/00007890-199601270-00028. [DOI] [PubMed] [Google Scholar]
  47. Wu T. C., Hruban R. H., Ambinder R. F., Pizzorno M., Cameron D. E., Baumgartner W. A., Reitz B. A., Hayward G. S., Hutchins G. M. Demonstration of cytomegalovirus nucleic acids in the coronary arteries of transplanted hearts. Am J Pathol. 1992 Mar;140(3):739–747. [PMC free article] [PubMed] [Google Scholar]
  48. Wu T. C., Kanayama M. D., Hruban R. H., Whitehead W., Raj N. B. Detection of a neuron-specific 9.0-kb transcript which shares homology with antisense transcripts of HIV-1 gag gene in patients with and without HIV-1 infection. Am J Pathol. 1993 Jan;142(1):25–31. [PMC free article] [PubMed] [Google Scholar]
  49. Xie Q. W., Cho H. J., Calaycay J., Mumford R. A., Swiderek K. M., Lee T. D., Ding A., Troso T., Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992 Apr 10;256(5054):225–228. doi: 10.1126/science.1373522. [DOI] [PubMed] [Google Scholar]
  50. Yang X., Chowdhury N., Cai B., Brett J., Marboe C., Sciacca R. R., Michler R. E., Cannon P. J. Induction of myocardial nitric oxide synthase by cardiac allograft rejection. J Clin Invest. 1994 Aug;94(2):714–721. doi: 10.1172/JCI117390. [DOI] [PMC free article] [PubMed] [Google Scholar]

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