[en] Aim: Cardiotrophin-1 (CT-1) is upregulated by hypoxemia and hemodynamic overload and is characterized by potent hypertrophic and protective properties on cardiac cells. This study aimed to investigate whether CT-1 is differentially induced in the myocardium of infants with congenital cardiac defects depending on hypoxemia. Methods & results: Infants with Tetralogy of Fallot (n = 8) or with large nonrestrictive ventricular septal defect (n = 8) undergoing corrective surgery were investigated. Expression of CT-1 was assessed at mRNA and protein levels in the right atrial and ventricular myocardium. The activation of the STAT-3 and VEGF were measured. Degradation of cardiac troponin-I served as a marker of myocardial damage. CT-1 was detected in all patients with levels negatively correlating to the arterial oxygen saturation. Higher CT-1 expression in Tetralogy of Fallot patients was associated with activation of the JAK/STAT pathway and higher cardiac troponin-I degradation. Conclusion: CT-1 may mediate myocardial hypertrophy and dysfunction in infants with congenital cardiac defects, particularly in those with hypoxemia.
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(9), 5783-5791 (1997
Potter DD, Araoz PA, Ng Ll et al. Cardiotropin 1 and myocardial strain change heterogeneously in cardiomyopathy. J. Surg. Res. 141(2), 277-283 (2007
Calabro P, Limongelli G, Riegler L et al. Novel insights into the role of cardiotrophin 1 in cardiovascular diseases. J. Mol. Cell Cardiol. 46(2), 142-148 (2009
Latchman DS. Cardiotrophin 1: A novel cytokine and its effects in the heart and other tissues. Pharmacol. Ther. 85(1), 29-37 (2000
Ichiki T, Jougasaki M, Setoguchi M et al. Cardiotrophin 1 stimulates intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 in human aortic endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 294(2), H750-H763 (2008
Lu Y, Zhou J, Xu C et al. JAK/STAT and PI3K/AKT pathways form a mutual transactivation loop and afford resistance to oxidative stress-induced apoptosis in cardiomyocytes. Cell. Physiol. Biochem. 21(4), 305-314 (2008
Gonzalez A, Ravassa S, Loperena I et al. Association of depressed cardiac gp130-mediated antiapoptotic pathways with stimulated cardiomyocyte apoptosis in hypertensive patients with heart failure. J. Hypertens. 25(10), 2148-2157 (2007
Malavazos AE, Ermetici F, Morricone L et al. Association of increased plasma cardiotrophin 1 with left ventricular mass indexes in normotensive morbid obesity. Hypertension 51(2), e8-e9; author reply e10 (2008
Talwar S, Downie PF, Squire IB, Barnett DB, Davies JD, Ng LL. An immunoluminometric assay for cardiotrophin 1: A newly identified cytokine is present in normal human plasma and is increased in heart failure. Biochem. Biophys. Res. Commun. 261(3), 567-571 (1999
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(1), 83-88 (2000
Ng LL, O'Brien RJ, Demme B, Jennings S. Non-competitive immunochemiluminometric assay for cardiotrophin 1 detects elevated plasma levels in human heart failure. Clin. Sci. (Lond.) 102(4), 411-416 (2002
Talwar S, Squire IB, Davies JE, Ng LL. The effect of valvular regurgitation on plasma cardiotrophin 1 in patients with normal left ventricular systolic function. Eur. J. Heart Fail. 2(4), 387-391 (2000
Zolk O, Engmann S, Munzel F, Krajcik R. Chronic cardiotrophin 1 stimulation impairs contractile function in reconstituted heart tissue. Am. J. Physiol. Endocrinol. Metab. 288(6), e1214-e1221 (2005
Asai S, Saito Y, Kuwahara K et al. The heart is a source of circulating cardiotrophin 1 in humans. Biochem. Biophys. Res. Commun. 279(2), 320-323 (2000
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(2), 436-440 (1999
Pan J, Fukuda K, Saito M et al. Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ. Res. 84(10), 1127-1136 (1999
Qing M, Nimmesgern A, Heinrich PC et al. Intrahepatic synthesis of tumor necrosis factor-alpha related to cardiac surgery is inhibited by interleukin 10 via the Janus kinase (JAK)/signal transducers and activator of transcription (STAT) pathway. Crit. Care Med. 31(12), 2769-2775 (2003
Freed DH, Moon MC, Borowiec AM, Jones SC, Zahradka P, Dixon IM. Cardiotrophin 1: Expression in experimental myocardial infarction and potential role in post-MI wound healing. Mol. Cell Biochem. 254(1-2), 247-256 (2003
Aoyama T, Takimoto Y, Pennica D et al. 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(10), 1821-1830 (2000
Qing M, Schumacher K, Heise R et al. Intramyocardial synthesis of pro-and anti-inflammatory cytokines in infants with congenital cardiac defects. J. Am. Coll. Cardiol. 41(12), 2266-2274 (2003
Qing M, Gorlach A, Schumacher K et al. The hypoxia-inducible factor HIF 1 promotes intramyocardial expression of VEGF in infants with congenital cardiac defects. Basic Res. Cardiol. 102(3), 224-232 (2007
Kunisada K, Tone E, Fujio Y, Matsui H, Yamauchi-Takihara K, Kishimoto T. Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation 98(4), 346-352 (1998
Lee KS, Park JH, Lee S, Lim HJ, Choi HE, Park HY. HB-EGF induces delayed STAT3 activation via NF kappaB mediated IL 6 secretion in vascular smooth muscle cell. Biochim. Biophys. Acta 1773(11), 1637-1644 (2007
Kunisada K, Negoro S, Tone E et al. Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc. Natl Acad. Sci. USA 97(1), 315-319 (2000
Funamoto M, Fujio Y, Kunisada K et al. Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes. J. Biol. Chem. 275(14), 10561-10566 (2000
Palmer BS, Klawitter PF, Reiser PJ, Angelos MG. Degradation of rat cardiac troponin I during ischemia independent of reperfusion. Am. J. Physiol. Heart Circ. Physiol. 287(3), H1269-H1275 (2004
McDonough JL, Arrell DK, Van Eyk JE. Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury. Circ. Res. 84(1), 9-20 (1999
Wollert KC, Taga T, Saito M et al. Cardiotrophin 1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series via gp130/leukemia inhibitory factor receptor-dependent pathways. J. Biol. Chem. 271(16), 9535-9545 (1996
Freed DH, Borowiec AM, Angelovska T, Dixon IM. Induction of protein synthesis in cardiac fibroblasts by cardiotrophin 1: Integration of multiple signaling pathways. Cardiovasc. Res. 60(2), 365-375 (2003
Freed DH, Cunnington RH, Dangerfield AL, Sutton JS, Dixon IM. Emerging evidence for the role of cardiotrophin 1 in cardiac repair in the infarcted heart. Cardiovasc. Res. 65(4), 782-792 (2005
