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Cardiotrophin-1: Expression in experimental myocardial infarction and potential role in post-MI wound healing

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Abstract

Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, has been shown to be elevated in the serum of patients with ischemic heart disease and valvular heart disease, and induces cardiomyocyte hypertrophy in vitro. We investigated expression of CT-1 in post-MI rat heart and the effect of CT-1 on cultured primary adult rat cardiac fibroblasts. Elevated CT-1 expression was observed in the infarct zone at 24 h and continued through 2, 4 and 8 weeks post-MI, compared to sham-operated animals. CT-1 induced rapid phosphorylation of Jak1, Jak2, STAT1, STAT3, p42/44 MAPK and Akt in cultured adult cardiac fibroblasts. CT-1 induced cardiac fibroblast protein synthesis and proliferation. Protein and DNA synthesis were dependent on activation of Jak/STAT, MEK1/2, PI3K and Src pathways as evidenced by decreased 3H-leucine and 3H-thymidine incorporation after pretreatment with AG490, PD98059, LY294002 and genistein respectively. Furthermore, CT-1 treatment increased procollagen-1-carboxypropeptide (P1CP) synthesis, a marker of mature collagen synthesis. CT-1 induced cell migration of rat cardiac fibroblasts. Our results suggest that CT-1, as expressed in post-MI heart, may play an important role in infarct scar formation and ongoing remodeling of the scar. CT-1 was able to initiate each of the processes considered important in the formation of infarct scar including cardiac fibroblast migration as well as fibroblast proliferation and collagen synthesis. Further work is required to determine factors that induce CT-1 expression and interplay with other mediators of cardiac infarct wound healing in the setting of acute cardiac ischemia and chronic post-MI heart failure.

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References

  1. Frangogiannis NG, Smith CW, Entman ML: The inflammatory response in myocardial infarction. Cardiovasc Res 53: 31-47, 2002

    Google Scholar 

  2. Sun Y, Weber KT: Infarct scar: A dynamic tissue. Cardiovasc Res 46: 250-256, 2000

    Google Scholar 

  3. McInnes GT: Clinical potential: Angiotensin converting enzyme inhibitor or angiotensin II antagonist? J Hypertens 19(suppl 1): S61-S67, 2001

    Google Scholar 

  4. Bouzegrhane F, Thibault G: Is angiotensin II a proliferative factor of cardiac fibroblasts? Cardiovasc Res 53: 304-312, 2002

    Google Scholar 

  5. Wei GC, Sirois MG, Qu R, Liu P, Rouleau JL: Subacute and chronic effects of quinapril on cardiac cytokine expression, remodeling, and function after myocardial infarction in the rat. J Cardiovasc Pharmacol 39: 842-850, 2002

    Google Scholar 

  6. Sano M, Fukuda K, Kodama H, Pan J, Saito M, Matsuzaki J, Takahashi T, Makino S, Kato T, Ogawa S: Interleukin-6 family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes. J Biol Chem 275: 29717-29723, 2000

    Google Scholar 

  7. Schultz JJ, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, Kimball TR, Doetschman T: TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 109: 787-796, 2002

    Google Scholar 

  8. Yu CM, Tipoe GL, Wing-Hon LK, Lau CP: Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction. J Am Coll Cardiol 38: 1207-1215, 2001

    Google Scholar 

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

    Google Scholar 

  10. Pennica D, King KL, Shaw KJ, Luis E, Rullamas J, Luoh SM, Darbonne WC, Knutzon DS, Yen R, Chien KR: Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci USA 92: 1142-1146, 1995

    Google Scholar 

  11. Ishikawa M, Saito Y, Miyamoto Y, Harada M, Kuwahara K, Ogawa E, Nakagawa O, Hamanaka I, Kajiyama N, Takahashi N, Masuda I, Hashimoto T, Sakai O, Hosoya T, Nakao K: A heart-specific increase in cardiotrophin-1 gene expression precedes the establishment of ventricular hypertrophy in genetically hypertensive rats. J Hypertens 17: 807-816, 1999

    Google Scholar 

  12. Liao Z, Brar BK, Cai Q, Stephanou A, O'Leary RM, Pennica D, Yellon DM, Latchman DS: Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischaemia and at reperfusion. Cardiovasc Res 53: 902-910, 2002

    Google Scholar 

  13. Robledo O, Fourcin M, Chevalier S, Guillet C, Auguste P, Pouplard-Barthelaix A, Pennica D, Gascan H: Signaling of the cardiotrophin-1 receptor. Evidence for a third receptor component. J Biol Chem 272: 4855-4863, 1997

    Google Scholar 

  14. Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR: Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem 272: 5783-5791, 1997

    Google Scholar 

  15. Kuwahara K, Saito Y, Kishimoto I, Miyamoto Y, Harada M, Ogawa E, Hamanaka I, Kajiyama N, Takahashi N, Izumi T, Kawakami R, Nakao K: Cardiotrophin-1 phosphorylates akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes. J Mol Cell Cardiol 32: 1385-1394, 2000

    Google Scholar 

  16. Talwar S, Squire IB, Downie PF, Davies JE, Ng LL: Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina. Heart 84: 421-424, 2000

    Google Scholar 

  17. Talwar S, Squire IB, O'Brien RJ, Downie PF, Davies JE, Ng LL: Plasma cardiotrophin-1 following acute myocardial infarction: Relationship with left ventricular systolic dysfunction. Clin Sci (Lond) 102: 9-14, 2002

    Google Scholar 

  18. Talwar S, Squire IB, Downie PF, O'Brien RJ, Davies JE, Ng LL: Elevated circulating cardiotrophin-1 in heart failure: Relationship with parameters of left ventricular systolic dysfunction. Clin Sci (Lond) 99: 83-88, 2000

    Google Scholar 

  19. Aoyama T, Takimoto Y, Pennica D, Inoue R, Shinoda E, Hattori R, Yui Y, Sasayama S: Augmented expression of cardiotrophin-1 and its receptor component, gp130, in both left and right ventricles after myocardial infarction in the rat. J Mol Cell Cardiol 32: 1821-1830, 2000

    Google Scholar 

  20. Dixon IMC, Lee SL, Dhalla NS: Nitrendipine binding in congestive heart failure due to myocardial infarction. Circ Res 66: 782-788, 1990

    Google Scholar 

  21. Hao J, Wang B, Jones SC, Jassal DS, Dixon IMC: Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol 279: H3020-H3030, 2000

    Google Scholar 

  22. Peterson DJ, Ju H, Hao J, Panagia M, Chapman DC, Dixon IM: Expression of Gi-2 alpha and Gs alpha in myofibroblasts localized to the infarct scar in heart failure due to myocardial infarction. Cardiovasc Res 41: 575-585, 1999

    Google Scholar 

  23. Saward L, Zahradka P: Coronary artery smooth muscle in culture: Migration of heterogeneous cell populations from vessel wall. Mol Cell Biochem 176: 53-59, 1997

    Google Scholar 

  24. Wolf G, Neilson EG: Angiotensin II induces cellular hypertrophy in cultured murine proximal tubular cells. Am J Physiol 259: 768-777, 1990

    Google Scholar 

  25. Nacher M, Serrano S, Marinoso ML, Garcia MC, Bosch J, Diez A, Lloreta J, Aubia J: In vitro synthesis of type I collagen: Quantification of carboxyterminal propeptide of procollagen type I vs. tritiated proline incorporation. Calcif Tissue Int 64: 224-228, 1999

    Google Scholar 

  26. Richards KL, McCullough J: A modified microchamber method for chemotaxis and chemokinesis. Immunol Commun 13: 49-62, 1984

    Google Scholar 

  27. Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM: Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379: 645-648, 1996

    Google Scholar 

  28. Davies SP, Reddy H, Caivano M, Cohen P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351: 95-105, 2000

    Google Scholar 

  29. Dixon RA, Ferreira D: Genistein. Phytochemistry 60: 205-211, 2002

    Google Scholar 

  30. Tsuruda T, Jougasaki M, Boerrigter G, Huntley BK, Chen HH, D'Assoro AB, Lee SC, Larsen AM, Cataliotti A, Burnett JC Jr: Cardiotrophin-1 stimulation of cardiac fibroblast growth: Roles for glycoprotein 130/leukemia inhibitory factor receptor and the endothelin type A receptor. Circ Res 90: 128-134, 2002

    Google Scholar 

  31. Thibault G, Lacombe MJ, Schnapp LM, Lacasse A, Bouzeghrane F, Lapalme G: Upregulation of alpha(8)beta(1)-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-beta1. Am J Physiol Cell Physiol 281: C1457-C1467, 2001

    Google Scholar 

  32. Pan J, Fukuda K, Saito M, Matsuzaki J, Kodama H, Sano M, Takahashi T, Kato T, Ogawa S: Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res 84: 1127-1136, 1999

    Google Scholar 

  33. Funamoto M, Hishinuma S, Fujio Y, Matsuda Y, Kunisada K, Oh H, Negoro S, Tone E, Kishimoto T, Yamauchi-Takihara K: Isolation and characterization of the murine cardiotrophin-1 gene: Expression and norepinephrine-induced transcriptional activation. J Mol Cell Cardiol 32: 1275-1284, 2000

    Google Scholar 

  34. Hishinuma S, Funamoto M, Fujio Y, Kunisada K, Yamauchi-Takihara K: Hypoxic stress induces cardiotrophin-1 expression in cardiac myocytes. Biochem Biophys Res Commun 264: 436-440, 1999

    Google Scholar 

  35. Latchman DS: Cardiotrophin-1 (CT-1): A novel hypertrophic and cardioprotective agent. Int J Exp Pathol 80: 189-196, 1999

    Google Scholar 

  36. Murphy M, Dutton R, Koblar S, Cheema S, Bartlett P: Cytokines which signal through the LIF receptor and their actions in the nervous system. Prog Neurobiol 52: 355-378, 1997

    Google Scholar 

  37. Ghosh AK: Factors involved in the regulation of type I collagen gene expression: Implication in fibrosis. Exp Biol Med (Maywood) 227: 301-314, 2002

    Google Scholar 

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Authors and Affiliations

  1. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, R2H 2A6

    Darren H. Freed, Michael C. Moon, Anna M. Borowiec, Stephen C. Jones, Peter Zahradka & Ian M.C. Dixon

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  1. Darren H. Freed
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  2. Michael C. Moon
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  6. Ian M.C. Dixon
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Freed, D.H., Moon, M.C., Borowiec, A.M. et al. Cardiotrophin-1: Expression in experimental myocardial infarction and potential role in post-MI wound healing. Mol Cell Biochem 254, 247–256 (2003). https://doi.org/10.1023/A:1027332504861

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