Abstract
Cytokines from the interleukin-6 (IL-6) family have been reported to play an important synergistic role with angiotensin II in the development of pathological cardiac hypertrophy. Whether their expression pattern changes in vivo, in an angiotensin II-dependent hypertrophied myocardium has not been reported. In this study, we addressed that issue using two animal models of angiotensin II-dependent cardiac hypertrophy. Heterozygous transgenic TGR(mRen2)27 (TGR) with an overactive cardiac renin angiotensin system and the closely related spontaneously hypertensive rats (SHR) were compared to their respective control rats. The mRNA levels of IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1) as well as their receptor subunits, glycoprotein 130 (gp130), IL-6 receptor (IL-6R), LIFR, and CNTFR, were measured by semi-quantitative RT-PCR. The protein levels of IL-6, LIF and CT-1 were investigated by western blot. TGR and SHR both displayed significant over expression of mRNA and protein levels for IL-6 and LIF. In TGR, the increased level of LIF was accompanied by a decrease in mRNA levels for LIFR and CNTFR. In SHR, a higher level of mRNA IL-6R was observed. By contrast, the mRNA and protein levels for CT-1 and the mRNA level for gp130 did not vary in these two models. These findings suggest that IL-6 and LIF, but not CT-1, contribute to angiotensin II-dependent left ventricular hypertrophy in the two hypertensive rat models, TGR(mRen2)27 and SHR. (Mol Cell Biochem 269: 95–101, 2005)
Similar content being viewed by others
References
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med 322: 1561–1566, 1990
Ruwhof C, van der Laarse A: Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res 47: 23–37, 2000
Swynghedauw B: Molecular mechanisms of myocardial remodeling. Physiol Rev 79: 215–262, 1999
Dahlof B: The importance of the renin-angiotensin system in reversal of left ventricular hypertrophy. J Hypertens 11: S29–S35, 1993
Booz GW, Dostal DE, Baker KM: Paracrine actions of cardiac fibroblasts on cardiomyocytes: Implications for the cardiac renin-angiotensin system. Am J Cardiol 83: 44H–47H, 1999
Wang F, Seta Y, Baumgarten G, Engel DJ, Sivasubramanian N, Mann DL: Functional significance of hemodynamic overload-induced expression of leukemia-inhibitory factor in the adult mammalian heart. Circulation 103: 1296–1302, 2001
Pennica D, King KL, Shaw KJ, Luis E, Rullamas J, Luoh SM, Darbonne WC, Knutzon DS, Yen R, Chien KR, Baker JB, Wood WI: Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci 92: 1142–1146, 1995
Wollert KC, Chien KR: Cardiotrophin-1 and the role of gp130-dependent signaling pathways in cardiac growth and development. J Mol Med 75: 492–501, 1997
Fukuzawa J, Booz GW, Hunt RA, Shimizu N, Karoor V, Baker KM, Dostal DE: Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes throughSTAT3: An autocrine loop for hypertrophy. Hypertension 35: 1191–1196, 2000
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
Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L: Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334: 297–314, 1998
Kishimoto T, Akira S, Narazaki M, Taga T: Interleukin-6 family of cytokines and gp130. Blood 86: 1243–1254, 1995
Kishimoto T, Tanaka T, Yoshida K, Akira S, Taga T: Cytokine signal transduction through a homo- or heterodimer of gp130. Ann NY Acad Sci 766: 224–234, 1995
Hirota H, Chen J, Betz UA, Rajewsky K, Gu Y, Ross J Jr, Muller W, Chien KR: Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97: 189–198, 1999
Mullins JJ, Peters J, Ganten D: Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 344: 541–544, 1990
Campbell DJ, Rong P, Kladis A, Rees B, Ganten D, Skinner SL: Angiotensin and bradykinin peptides in the TGR mRen-2 27 rat. Hypertension 25: 1014–1020, 1995
Ohta K, Kim S, Wanibuchi H, Ganten D, Iwao H: Contribution of local renin-angiotensin system to cardiac hypertrophy, phenotypic modulation, and remodeling in TGR mRen2 27 transgenic rats. Circulation 94: 785–791, 1996
Sano H, Okamoto H, Kitabatake A, Iizuka K, Murakami T, Kawaguchi H: Increased mRNA expression of cardiac renin-angiotensin system and collagen synthesis in spontaneously hypertensive rats. Mol Cell Biochem 178: 51–58, 1998
Jurkovicova D, Dobesova Z, Kunes J, Krizanova O: Different expression of renin-angiotensin system components in hearts of normotensive and hypertensive rats. Physiol Res 50: 35–42, 2001
Mizuno K, Tani M, Hashimoto S, Niimura S, Sanada H, Watanabe H, Ohtsuki M, Fukuchi S: Effects of losartan, a nonpeptide angiotensin II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats. Life Sci 51: 367–374, 1992
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
Pan J, Fukuda K, Kodama H, Sano M, Takahashi T, Makino S, Kato T, Manabe T, Hori S, Ogawa S: Involvement of gp130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart. Heart Vessels 13: 199–208, 1998
Kurdi M, Dizerens N, Cerutti C, Bricca G, Randon J: Expression des cytokines et de leurs récepteurs dans le ventricule gauche hypaertrophique du rat TGR mRen2 27. Arch Mal Coeur Vaiss 96: 811–814, 2003
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
Takimoto Y, Aoyama T, Iwanaga Y, Izumi T, Kihara Y, Pennica D, Sasayama S: Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats. Am J Physiol 282: H896–H901, 2002
Lee MA, Bohm M, Paul M, Bader M, Ganten U, Ganten D: Physiological characterization of the hypertensive transgenic rat TGR mREN2 27. Am J Physiol 270: 919–929, 1996
Ohta K, Kim S, Iwao H: Role of angiotensin-converting enzyme, adrenergic receptors, and blood pressure in cardiac gene expression of spontaneously hypertensive rats during development. Hypertension 28: 627–634, 1996
Tone E, Kunisada K, Kumanogoh A, Negoro S, Funamoto M, Osugi T, Kishimoto T, Yamauchi-Takihara K: gp130-Dependent signalling pathway is not enhanced in gp130 transgenic heart after LIF stimulation. Cytokine 12: 1512–1518, 2000
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 92: 4862–4866, 1995
Molkentin JD, Dorn II GW: Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol 63: 391–426, 2001
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kurdi, M., Randon, J., Cerutti, C. et al. Increased expression of IL-6 and LIF in the hypertrophied left ventricle of TGR(mRen2)27 and SHR rats. Mol Cell Biochem 269, 95–101 (2005). https://doi.org/10.1007/s11010-005-3085-1
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11010-005-3085-1