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Norepinephrine-induced cardiac hypertrophy and fibrosis are not due to mast cell degranulation

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Abstract

The norepinephrine (NE)-induced hypertrophy of the left ventricle (LV) in the rat is preceded by increased interleukin (IL)-6 expression and associated with LV fibrosis. We have examined whether the elevated level of IL-6 may be due to mast cell degranulation. Therefore we tested the effect of cromoglycate sodium salt (cromolyn), an inhibitor of mast cell degranulation with anti-inflammatory and membrane-stabilizing activity, on the increased expression of IL-6 mRNA and of mRNAs of proteins involved in the remodelling of the extracellular matrix (ECM) which is induced by NE (0.1 mg/kg·h). After 4 h, the NE-induced increase in IL-6 mRNA expression was not influenced by cromolyn (20 mg/kg·h). Cromolyn-infusion for 3 days did not affect the extent of LV hypertrophy induced by NE, as measured by the LV weight/body weight (LVW/BW) ratio and by atrial natriuretic peptide (ANP) expression. Cromolyn induced a slight depression of the NE-induced elevation of the matrix metalloproteinase (MMP)-2. However, it did not affect the NE-induced elevated levels of mRNAs of collagen I and III and the tissue inhibitor of matrix metalloproteinase (TIMP)-2. Since cromolyn did not reduce the NE-effects in rat hearts in vivo we conclude that mast cell degranulation seems not to be involved in them.

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References

  1. Dvorak AM: Mast-cell degranulation in human hearts. N Engl J Med 315: 969-970, 1986

    Google Scholar 

  2. Marone G, de Crescenzo G, Adt M, Patella V, Arbustini E, Genovese A: Immunological characterization and functional importance of human heart mast cells. Immunopharmacology 31: 1-18, 1995

    Google Scholar 

  3. Panizo A, Mindan FJ, Galindo MF, Cenarruzabeitia E, Hernandez M, Diez J: Are mast cells involved in hypertensive heart disease? J Hypertens 13: 1201-1208, 1995

    Google Scholar 

  4. Patella V, Marino I, Arbustini E, Lamparter-Schummert B, Verga L, Adt M, Marone G: Stem cell factor in mast cells and increased mast cell density in idiopathic and ischemic cardiomyopathy. Circulation 97: 971-978, 1998

    Google Scholar 

  5. Keller AM, Clancy RM, Barr ML, Marboe CC, Cannon PJ: Acute reoxygenation injury in the isolated rat heart: Role of resident cardiac mast cells. Circ Res 63: 1044-1052, 1988

    Google Scholar 

  6. Estensen RD: What is the role of myocardial mast cells? Hum Pathol 16: 536-538, 1985

    Google Scholar 

  7. Williams RM, Bienenstock J, Stead RH: Mast cells: The neuroimmune connection. Chem Immunol 61: 208-235, 1995

    Google Scholar 

  8. Galli SJ: New concepts about the mast cell. N Engl J Med 328: 257-265, 1993

    Google Scholar 

  9. Marone G, Casolaro V, Cirillo R, Stellato C, Genovese A: Pathophysiology of human basophils and mast cells in allergic disorders. Clin Immunol Immunopathol 50: S24-S40, 1989

    Google Scholar 

  10. Olivetti G, Lagrasta C, Ricci R, Sonnenblick EH, Capasso JM, Anversa P: Long-term pressure-induced cardiac hypertrophy: Capillary and mast cell proliferation. Am J Physiol 257: H1766-H1772, 1989

    Google Scholar 

  11. Stevens RL, Austen KF: Recent advances in the cellular and molecular biology of mast cells. Immunol Today 10: 381-386, 1989

    Google Scholar 

  12. Vigorito C, Giordano A, De Caprio L, Vitale DF, Maurea N, Silvestri P, Tuccillo B, Ferrara N, Marone G, Rengo F: Effects of histamine on coronary hemodynamics in humans: Role of H1 and H2 receptors. J Am Coll Cardiol 10: 1207-1213, 1987

    Google Scholar 

  13. Okumura K, Yasue H, Matsuyama K, Matsuyama K, Morikami Y, Ogawa H, Obata K: Effect of H1 receptor stimulation on coronary artery diameter in patients with variant angina: Comparison with effect of acetylcholine. J Am Coll Cardiol 17: 338-345, 1991

    Google Scholar 

  14. Chester AH: Mast cells feel the strain. Cardiovasc Res 55: 13-15, 2002

    Google Scholar 

  15. Peitsch MC, Tschopp J: Assembly of macromolecular pores by immune defense systems. Curr Opin Cell Biol 3: 710-716, 1991

    Google Scholar 

  16. Gordon JR, Galli SJ: Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature 346: 274-276, 1990

    Google Scholar 

  17. Gordon JR, Burd PR, Galli SJ: Mast cells as a source of multifunctional cytokines. Immunol Today 11: 458-464, 1990

    Google Scholar 

  18. Leal-Berumen I, Conlon P, Marshall JS: IL-6 production by rat peritoneal mast cells is not necessarily preceded by histamine release and can be induced by bacterial lipopolysaccharide. J Immunol 152: 5468-5476, 1994

    Google Scholar 

  19. Möller A, Henz BM, Grützkau A, Lippert U, Aragane Y, Schwarz T, Krüger-Krasagakes S: Comparative cytokine gene expression: Regulation and release by human mast cells. Immunology 93: 289-295, 1998

    Google Scholar 

  20. Zierhut W, Zimmer H-G: Significance of myocardial alpha-and beta-adrenoceptors in catecholamine-induced cardiac hypertrophy. Circ Res 65: 1417-1425, 1989

    Google Scholar 

  21. Barth W, Deten A, Bauer M, Reinohs M, Leicht M, Zimmer H-G: Differential remodeling of the left and right heart after norepinephrine treatment in rats: Studies on cytokines and collagen. J Mol Cell Cardiol 32: 273-284, 2000

    Google Scholar 

  22. Bürger A, Benicke M, Deten A, Zimmer H-G: Catecholamines stimulate interleukin-6 synthesis in rat cardiac fibroblasts. Am J Physiol Heart Circ Physiol 281: H14-H21, 2001

    Google Scholar 

  23. Huang M, Pang X, Letourneau R, Boucher W, Theoharides TC: Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in Apolipoprotein E knockout mice. Cardiovasc Res 55: 150-160, 2002

    Google Scholar 

  24. Foreman JC: Neuropeptides and the pathogenesis of allergy. Allergy 42: 1-11, 1987

    Google Scholar 

  25. Dimitriadou V, Buzzi MG, Moskowitz MA, Theoharides TC: Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells. Neuroscience 44: 97-112, 1991

    Google Scholar 

  26. Theoharides TC, Spanos C, Pang X, Alferes L, Ligris K, Letourneau R, Rozniecki JJ, Webster E, Chrousos GP: Stress-induced intracranial mast cell degranulation: A corticotropin-releasing hormone-mediated effect. Endocrinology 136: 5745-5750, 1995

    Google Scholar 

  27. Pang X, Alexacos N, Letourneau R, Seretakis D, Gao W, Boucher W, Cochrane DE, Theoharides TC: A neurotensin receptor antagonist inhibits acute immobilization stress-induced cardiac mast cell degranulation, a corticotropin-releasing hormone-dependent process. J Pharmacol Exp Ther 287: 307-314, 1998

    Google Scholar 

  28. Parikh V, Singh M: Possible role of cardiac mast cells in norepinephrine-induced myocardial preconditioning. Methods Find Exp Clin Pharmacol 21: 269-274, 1999

    Google Scholar 

  29. Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156-159, 1987

    Google Scholar 

  30. Briest W, Hölzl A, Raßler B, Deten A, Leicht M, Baba HA, Zimmer H-G: Cardiac remodeling after long term norepinephrine treatment in rats. Cardiovasc Res 52: 265-273, 2001

    Google Scholar 

  31. Hirota H, Yoshida K, Kishimoto T, Taga T: Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci USA 92: 4862-4866, 1995

    Google Scholar 

  32. Choi I, Kang HS, Yang Y, Pyun KH: IL-6 induces hepatic inflammation and collagen synthesis in vivo. Clin Exp Immunol 95: 530-535, 1994

    Google Scholar 

  33. Kondo K, Okada T, Matsui T, Kato S, Date K, Yoshihara M, Nagata Y, Takagi H, Yoneda M, Sugie I: Establishment and characterization of a human B cell line from the lung tissue of a patient with scleroderma; extraordinary high level of IL-6 secretion by stimulated fibroblasts. Cytokine 13: 220-226, 2001

    Google Scholar 

  34. Xue H, McCauley RL, Zhang W: Elevated interleukin-6 expression in keloid fibroblasts. J Surg Res 89: 74-77, 2000

    Google Scholar 

  35. Yue P, Massie BM, Simpson PC, Long CS: Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. Am J Physiol 275: H250-H258, 1998

    Google Scholar 

  36. Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S: Cytokine gene expression after myocardial infarction in rat hearts: Possible implication in left ventricular remodeling. Circulation 98: 149-156, 1998

    Google Scholar 

  37. Aragane Y, Riemann H, Bhardwaj RS, Schwarz A, Sawada Y, Yamada H, Luger TA, Kubin M, Trinchieri G, Schwarz T: IL-12 is expressed and released by human keratinocytes and epidermoid carcinoma cell lines. J Immunol 153: 5366-5372, 1994

    Google Scholar 

  38. Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heusser CH, Howarth PH, Holgate ST: Interleukin-4,-5, and-6 and tumor necrosis factor-alpha in normal and asthmatic airways: Evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 10: 471-480, 1994

    Google Scholar 

  39. Worm M, Henz BM: Molecular regulation of human IgE synthesis. J Mol Med 75: 440-447, 1997

    Google Scholar 

  40. Raßler B, Barth W, Zimmer H-G: Transient pleural effusion in norepinephrine-stimulated rats. Basic Res Cardiol 96: 471-477, 2001

    Google Scholar 

  41. Yang M, Ruan J, Voller M, Schalken J, Michel MC: Differential regulation of human alpha1-adrenoceptor subtypes. Naunyn Schmiedebergs Arch Pharmacol 359: 439-446, 1999

    Google Scholar 

  42. Kurose H, Lefkowitz RJ: Differential desensitization and phosphorylation of three cloned and transfected alpha 2-adrenergic receptor subtypes. J Biol Chem 269: 10093-10099, 1994

    Google Scholar 

  43. Heck DA, Bylund DB: Differential down-regulation of alpha-2 adrenergic receptor subtypes. Life Sci 62: 1467-1472, 1998

    Google Scholar 

  44. Pearce FL: Mast cells: Function, differentiation and activation. Curr Opin Immunol 1: 630-636, 1989

    Google Scholar 

  45. Altounyan RE: Review of clinical activity and mode of action of sodium cromoglycate. Clin Allergy 10(suppl): 481-489, 1980

    Google Scholar 

  46. Theoharides TC, Sieghart W, Greengard P, Douglas WW: Antiallergic drug cromolyn may inhibit histamine secretion by regulating phosphorylation of a mast cell protein. Science 207: 80-82, 1980

    Google Scholar 

  47. Theoharides TC, Wang L, Pang X, Letourneau R, Culm KE, Basu S, Wang Y, Correia I: Cloning and cellular localization of the rat mast cell 78-kDa protein phosphorylated in response to the mast cell 'stabilizer’ cromolyn. J Pharmacol Exp Ther 294: 810-821, 2000

    Google Scholar 

  48. Klinker JF, Seifert R: Morphine and muscle relaxants are receptor-independent G-protein activators and cromolyn is an inhibitor of stimulated G-protein activity. Inflamm Res 46: 46-50, 1997

    Google Scholar 

  49. Laycock SK, McMurray J, Kane KA, Parratt JR: Effects of chronic norepinephrine administration on cardiac function in rats. J Cardiovasc Pharmacol 26: 584-589, 1995

    Google Scholar 

  50. De Bold AJ, Bruneau BG, Kuroski de Bold ML: Mechanical and neuroendocrine regulation of the endocrine heart. Cardiovasc Res 31: 7-18, 1996

    Google Scholar 

  51. Deten A, Volz HC, Briest W, Zimmer H-G: Cardiac cytokine expression is upregulated in the acute phase after myocardial infarction. Experimental studies in rats. Cardiovasc Res 55: 329-340, 2002

    Google Scholar 

  52. Deten A, Volz HC, Briest W, Zimmer H-G: Differential cytokine expression in myocytes and non-myocytes after myocardial infarction in rats. Mol Cell Biochem 242: 47-55, 2003

    Google Scholar 

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Authors and Affiliations

  1. Carl-Ludwig Institute of Physiology, University of Leipzig, Liebigstrasse 27, D-04103, Leipzig, Germany

    Wilfried Briest

  2. Carl-Ludwig Institute of Physiology, University of Leipzig, Leipzig, Germany

    Beate Raßler, Alexander Deten & Heinz-Gerd Zimmer

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  1. Wilfried Briest
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  2. Beate Raßler
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  3. Alexander Deten
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  4. Heinz-Gerd Zimmer
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Briest, W., Raßler, B., Deten, A. et al. Norepinephrine-induced cardiac hypertrophy and fibrosis are not due to mast cell degranulation. Mol Cell Biochem 252, 229–237 (2003). https://doi.org/10.1023/A:1025596404975

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