This Article Abstract Full Text (PDF) All Versions of this Article: 106/12/1442    most recent 01.CIR.0000033117.39335.DFv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zolk, O. Articles by Eschenhagen, T. Search for Related Content PubMed PubMed Citation Articles by Zolk, O. Articles by Eschenhagen, T. Related Collections Congestive Growth factors/cytokines Related Article

(Circulation. 2002;106:1442.)
© 2002 American Heart Association, Inc.

Brief Rapid Communications

Augmented Expression of Cardiotrophin-1 in Failing Human Hearts Is Accompanied by Diminished Glycoprotein 130 Receptor Protein Abundance

Oliver Zolk, MD; Leong L. Ng, MD; Russell J. O’Brien, MB; Michael Weyand, MD; Thomas Eschenhagen, MD

From the Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (O.Z., T.E.); the Department of Medicine and Therapeutics, University of Leicester, Leicester, United Kingdom (L.L.N., R.J.O.); and Zentrum für Herzchirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (M.W.).

Correspondence to Dr Oliver Zolk, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany. E-mail Zolk{at}pharmakologie.uni-erlangen.de

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, is a potent inducer of cardiomyocyte hypertrophy that prolongs myocyte survival. Although cardiac CT-1 gene expression is known to be upregulated in some animal models of congestive heart failure, the activation state of the CT-1 system in patients with congestive heart failure is unknown.

Methods and Results— This study was designed to determine left ventricular expression of CT-1 and its glycoprotein 130 (gp130)/leukemia inhibitory factor receptor complex in human end-stage heart failure due to ischemic and dilated cardiomyopathy. In addition, we investigated the activation state of signal transducer and activator of transcription 3 (STAT3), the downstream effector of gp130 signaling. In the failing left ventricular myocardium, expression levels of CT-1 mRNA and protein were significantly increased by 142% and 68%, respectively, compared with non-failing donor hearts. Immunohistochemistry confirmed the increased expression of CT-1 in cardiac myocytes. Although gp130 gene expression was increased by 91% (P<0.001), gp130 protein abundance was significantly diminished by 34% in the failing myocardium. In contrast, leukemia inhibitory factor receptor and suppressor of cytokine signaling-3 protein concentrations were not changed. In addition, the ratio of activated tyrosine phosphorylated STAT3 to total STAT3 was not significantly altered in failing hearts compared with non-failing controls.

Conclusions— Our data suggest that gp130 receptor downregulation balances enhanced CT-1 expression in human heart failure and thereby inhibits excessive activation of the gp130 signaling pathway.

Key Words: genes • heart failure • growth substances • receptors • signal transduction

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Heart failure is the leading cause of mortality that ensues after the chronic activation of biomechanical stress pathways that results from various forms of cardiac injury.

See p 1430

The myocardium first develops adaptive, compensatory hypertrophy, which ultimately leads to an irreversible decompensation in cardiac function. Although the molecular mechanisms that may promote or, conversely, inhibit the transition from compensatory hypertrophy to heart failure are unknown, recent evidence suggests an important role for cardiotrophin-1 (CT-1). CT-1 belongs to the interleukin-6 (IL-6) family of cytokines.¹ CT-1 binds to the glycoprotein 130 (gp130)/leukemia inhibitory factor (LIF) receptor complex² and activates both mitogen-activated protein kinase and janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways.³ Through these pathways, CT-1 induces hypertrophy and prolongs survival of cardiomyocytes.³ Excessive CT-1 signaling is efficiently attenuated by negative feedback mechanisms. These include gp130 receptor internalization and degradation and induction of intrinsic suppressor of cytokine signaling (SOCS) proteins, such as SOCS-3.⁴

We and others have shown that patients with congestive heart failure have raised plasma levels of CT-1^5–7 that correspond to disease severity.⁶ Enhanced CT-1 secretion seems to be an early event that occurs before onset of left ventricular systolic dysfunction and therefore may have an impact on disease progression.⁸ The observation that CT-1 concentrations were significantly higher in the coronary sinus than in the aorta⁹ indicates that the heart is a prominent source of circulating CT-1 in humans. In the present study, we defined cardiac expression levels of CT-1 in donor hearts and explanted hearts from patients with end-stage heart failure. Moreover, we addressed the question of whether negative feedback mechanisms, such as a loss of gp130/LIF receptor protein or induction of SOCS-3, were relevant in human heart failure.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Human Cardiac Tissue
Failing hearts were obtained from patients undergoing orthotopic heart transplantation because of end-stage heart failure (New York Heart Association functional class III to IV) that resulted from idiopathic dilated cardiomyopathy or ischemic cardiomyopathy (diagnosis made by coronary angiography). All patients gave written informed consent before surgery. Myocardial tissue from 8 non-failing donor hearts that could not be transplanted because of surgical reasons or blood group incompatibility were studied for comparison. Neither the donor patient histories nor 2-dimensional echocardiography had revealed signs of heart disease (Table).

View this table: [in this window] [in a new window]   Patient Details

Northern Blot Analysis
For Northern blot analysis, polymerase chain reaction (PCR)-derived 608 bp and 996 bp fragments of human GAPDH cDNA and human gp130 cDNA, respectively, were used to generate specific probes.

Noncompetitive Immunoluminometric Assay for CT-1
The methodology for assay of CT-1 has been described previously.⁷ Approximately 100 mg of cardiac tissue was homogenized in 400 µL of buffer (consisting of 150 mmol/L NaCl, 50 mmol/L Tris pH 7.4, 1 mmol/L EDTA, 1 mmol/L PMSF, 1 µg/mL aprotinin, 1% Triton X-100 [Sigma]). After centrifugation, 20 µL of the extracts was assayed for CT-1 with standards in the range 1 to 20 fmol per well. Within and between assay coefficients of variation were 6.2% and 10.3%, respectively. CT-1 levels were determined by an investigator who was blinded to patient details. Each CT-1 value represents the mean of duplicate measurements and is expressed as pmol/mg protein.

Real-Time Reverse Transcriptase-PCR
Total RNA (2 µg) was reverse-transcribed with Moloney murine leukemia virus reverse transcriptase, and cDNA was subsequently amplified with the TaqMan system (Prism 7700, PE Biosystems). Primers and probes for CT-1 and GAPDH were designed to cross an intron/exon boundary (CT-1 forward 5'-CACTTGGAGGCC- AAGATCC-3', reverse 5'-TCTCCCTGGAGCTGCACAT-3', probe FAM-5'-TCAGACACACAGCCTTGCGCACCT-3'-TAMRA; GAPDH forward 5'-CTGCACCACCAACTGCTTAG-3', reverse 5'-GT-CTTCTGGGTGGCAGTGAT-3', probe FAM-5'-ATGGAC-TGTGGTCATGAGCCCTTCCA-TAMRA-3'), thereby eliminating the possibility of chromosomal DNA artifacts in the PCR. The level of GAPDH in each sample was used to normalize for the variability in RNA quantity or differences in the efficiency of the reverse transcriptase (RT)-reaction.

Western Blot Analysis
Proteins from human myocardium were extracted in 50 mmol/L Tris-HCl, pH 7.4, 150 mmol/L NaCl, 1 mmol/L EDTA, 1 mmol/L PMSF, 1 µg/mL aprotinin, and 1% Triton X-100, (for quantification of phosphoproteins, phosphatase inhibitors 1 mmol/L Na₃VO₄ and 1 mmol/L NaF were included) and separated by 10% SDS-PAGE. Membranes were blocked with 5% nonfat dried milk or 5% bovine serum albumin before incubation with polyclonal antibodies against human gp130, LIF receptor (LIFR) (Santa Cruz Biotechnology), SOCS-3 (Zymed), STAT3, and phospho-Tyr705-STAT3 (Cell Signaling), followed by horseradish peroxidase-conjugated anti-rabbit immunoglobulin G. Proteins were visualized using the enhanced chemiluminescence detection system (Amersham). The blots were also probed with a polyclonal calsequestrin antibody (Affinity Bioreagents) as a control for loading.

Immunohistochemistry
Immunohistochemistry was performed on cryostat sections (10 µm) with the Rabbit ABC Staining Kit (Santa Cruz Biotechnology) according to the manufacturer’s protocol. The primary antibody, reactive to amino acids 186 to 199 (SRTEGDLGQLLPGG) of the CT-1 sequence, was affinity purified on a Sepharose CL4B protein A column before using the immunoglobulin G fraction. Preabsorption of the antibody with excess immobilized CT-1 was found to eliminate the immunostaining.

Statistical Analysis
Data are presented as mean±SEM. Box plots show the median and 25th and 75th percentiles. Statistical analysis was performed using Student’s t test. A value of P<0.05 was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
CT-1 Expression Is Increased in Human Heart Failure
The protein and mRNA levels of CT-1 were analyzed in left ventricular (LV) myocardium from donor hearts and in failing LV myocardium from patients with dilated or ischemic cardiomyopathy (Figure 1). Real-time RT-PCR analysis revealed that the ratio of CT-1 mRNA/GAPDH mRNA normalized to non-failing controls increased from 1.0±0.23 to 2.1±0.2 (P<0.01) in failing hearts. CT-1 protein was detectable by immunohistochemistry in failing hearts, as shown in Figure 2. CT-1 immunoreactivity was predominantly observed in the cytoplasm of cardiomyocytes, but was also seen in non-myocyte cells, such as vascular smooth muscle cells. To quantify CT-1 concentrations in the left ventricular myocardium more accurately, immunoluminometric analyses of LV tissue extracts were performed. Augmented CT-1 transcript expression was paralleled by increased CT-1 protein concentrations in the failing myocardium (Figure 1), which were raised from 7.9±0.8 pmol/mg (n=8) to 13.2±0.8 pmol/mg (n=23, P<0.001) in hearts from ischemic cardiomyopathy and dilated cardiomyopathy patients.

View larger version (37K): [in this window] [in a new window]   Figure 1. CT-1 expression in left ventricles from patients with dilated and ischemic cardiomyopathy (CM) and from non-failing donor hearts (NF). A, Quantification of CT-1 mRNA by quantitative real-time RT-PCR. B, Immunohistochemical staining of CT-1 in left ventricular myocardium from a patient with dilated cardiomyopathy and in non-failing control myocardium (NF). Control staining was carried out with CT-1-preabsorbed antibody (IgG). CT-1 label was mainly detected on myocytes, but coronary vessels were also strongly stained (arrowhead). Magnification: x200. C, Immunoluminometric quantification of left ventricular CT-1.

View larger version (49K): [in this window] [in a new window]   Figure 2. A, Expression levels of major CT-1 signaling proteins in left ventricular myocardium from failing hearts (CM) and non-failing donor hearts (NF). A, Quantification of gp130 mRNA by Northern blot analysis. Left panel shows a representative blot; right panel shows the densitometric analysis. B, Expression levels of gp130, LIFR, and SOCS-3 protein, determined by Western blotting. Left panels show the representative blots; right panels show densitometric analysis. Calsequestrin Western blotting confirmed equal protein loading. C, Ratio of gp130/SOCS-3 protein expression, determined by Western blot analysis. D, Tyrosine phosphorylation of STAT3, determined by Western blot analysis with p-Tyr-STAT3 and total STAT3 antibodies. ICM indicates ischemic cardiomyopathy; DCM, idiopathic dilated cardiomyopathy.

LIF Receptor, gp130, and SOCS-3 Expression in Human Heart Failure
We examined expression levels of major CT-1 signaling molecules (Figure 2). Northern blot analysis revealed that gp130 gene expression was increased by 91% (gp130 mRNA/GAPDH mRNA 0.78±0.03, n=16, versus 0.41±0.05, n=8, P<0.001). Gp130 protein abundance, however, was diminished significantly by 34% (35.0±1.9, n=21, versus 52.9±2.6, n=8, P<0.001). In contrast, LIF receptor (9.4±0.5, n=21, versus 9.6±1.1, n=8) and SOCS-3 protein concentrations (16.4±1.6, n=21, versus 12.4±2.5, n=8) were not significantly changed. The gp130/SOCS-3 protein ratio was significantly decreased by 53% (Figure 2C)

Activation State of STAT3
To assess whether downregulation of the gp130 receptor subunit in failing hearts may change activation levels of downstream effector molecules, we determined the phosphorylation state of STAT3 (Figure 2D). The ratio of activated tyrosine phosphorylated STAT3 (p-Tyr-STAT3) to total STAT3 was not significantly changed in failing LV myocardium compared with non-failing hearts (0.69±0.09, n=21, versus 0.44±0.10, n=8). Preliminary experiments demonstrated that storage of human heart tissue on ice during transport to the laboratory led to dephosphorylation of STAT3 by less than 2.5%. Thus, we could exclude rapid dephosphorylation of STAT3 after explantation of the hearts, which could have affected our results.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study demonstrates for the first time that CT-1 gene expression and protein content are increased in failing human left ventricular myocardium. On the basis of the potent growth-promoting properties of CT-1 in vitro, this finding supports a potential role for CT-1 as a local paracrine/endocrine factor promoting cardiac hypertrophy via activation of gp130.

Gp130-induced hypertrophy in vitro is characterized by increased addition of sarcomeric units in series rather than in parallel, which has been linked to ventricular dilatation.¹⁰ Conversely, transgenic studies suggest that gp130 signaling may play an important role in the prevention of ventricular dilatation. Mice with a conditional heart-specific knock-out of gp130 present normal cardiac structure and function, but during acute pressure overload, the hearts of these mice display rapid onset of dilated cardiomyopathy and induction of myocyte apoptosis.¹¹ The protective action of CT-1 seems to be mediated through JAK-STAT signaling, as demonstrated in transgenic mice. Cardiac-specific overexpression of STAT3 provides protection against doxorubicin-induced cardiomyopathy, thus resulting in an improved survival rate by preventing progression of heart failure.¹² Altogether, these results suggest that preserved or even enhanced gp130/STAT3 signaling might delay onset of cardiac failure.

Does augmented CT-1, however, cause an activation of the gp130/STAT3 signaling in human end-stage heart failure? Gp130 protein was markedly decreased in the failing myocardium, despite augmented transcript expression. This was paralleled by an increase in the SOCS-3/gp130 protein ratio, which suggests an inactivation of the gp130 signaling pathway. Containment of gp130 signaling has been demonstrated for other IL-6 type cytokines like oncostatin (OSM), LIF, and IL-6.^4,13,14 This seems to be directed by 2 distinct mechanisms, the induction of factors, such as SOCS proteins, that attenuate functions of the cytoplasmic domain of gp130, and ligand-induced gp130 internalization and degradation, which is compensated, at least in part, by enhanced gp130 transcription.^13,14 The latter mechanism seems to be predominant in human heart failure. Steady state activation levels of STAT3, the downstream effector of gp130 signaling mediating myocyte hypertrophy and survival, was unchanged in failing ventricles compared with donor hearts. This finding suggest that gp130 receptor downregulation balances enhanced CT-1 in human heart failure and thereby inhibits excessive activation of the gp130 signaling pathway.

	Acknowledgments

 
This work was supported by the Deutsche Forschungsgemeinschaft (Zo 123/1–1). The authors thank Ingo Schubert and Pascal Haas for expert technical assistance.

Received June 5, 2002; revision received July 25, 2002; accepted July 26, 2002.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Pennica D, King KL, Shaw KJ, et al. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci U S A. 1995; 92: 1142–1146.[Abstract/Free Full Text]

2. Pennica D, Shaw KJ, Swanson TA, et al. Cardiotrophin-1: biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem. 1995; 270: 10915–10922.[Abstract/Free Full Text]

3. Sheng Z, Knowlton K, Chen J, et al. 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. 1997; 272: 5783–5791.[Abstract/Free Full Text]

4. Yasukawa H, Hoshijima M, Gu Y, et al. Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. J Clin Invest. 2001; 108: 1459–1467.[CrossRef][Medline] [Order article via Infotrieve]

5. Talwar S, Downie PF, Squire IB, et al. 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. 1999; 261: 567–571.[CrossRef][Medline] [Order article via Infotrieve]

6. Talwar S, Squire IB, Downie PF, et al. Elevated circulating cardiotrophin-1 in heart failure: relationship with parameters of left ventricular systolic dysfunction. Clin Sci. 2000; 99: 83–88.[Medline] [Order article via Infotrieve]

7. Ng LL, O’Brien RJ, Demme B, et al. Non-competitive immunochemiluminometric assay for cardiotrophin-1 detects elevated plasma levels in human heart failure. Clin Sci. 2002; 102: 411–416.[Medline] [Order article via Infotrieve]

8. Talwar S, Squire IB, Davies JE, et al. The effect of valvular regurgitation on plasma cardiotrophin-1 in patients with normal left ventricular systolic function. Eur J Heart Fail. 2000; 2: 387–291.[Abstract/Free Full Text]

9. Asai S, Saito Y, Kuwahara K, et al. The heart is a source of circulating cardiotrophin-1 in humans. Biochem Biophys Res Commun. 2000; 279: 320–323.[CrossRef][Medline] [Order article via Infotrieve]

10. 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. 1996; 271: 9535–9545.[Abstract/Free Full Text]

11. Hirota H, Chen J, Betz UA, et al. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1999; 97: 189–198.[CrossRef][Medline] [Order article via Infotrieve]

12. 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 U S A. 2000; 97: 315–319.[Abstract/Free Full Text]

13. Blanchard F, Wang Y, Kinzie E, et al. Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms. J Biol Chem. 2001; 276: 47038–47045.[Abstract/Free Full Text]

14. Greenhalgh CJ, Hilton DJ. Negative regulation of cytokine signaling. J Leukoc Biol. 2001; 70: 348–356.[Abstract/Free Full Text]

Related Article:

Cardiotrophin-1 in Heart Failure

Michael R. Bristow and Carlin S. Long
Circulation 2002 106: 1430-1432. [Extract] [Full Text]

This article has been cited by other articles:

				K. R. McGaffin, C. S. Moravec, and C. F. McTiernan Leptin Signaling in the Failing and Mechanically Unloaded Human Heart Circ Heart Fail, November 1, 2009; 2(6): 676 - 683. [Abstract] [Full Text] [PDF]

				D. J. Hausenloy and D. M. Yellon Cardioprotective growth factors Cardiovasc Res, July 15, 2009; 83(2): 179 - 194. [Abstract] [Full Text] [PDF]

				N. Lopez-Andres, C. Inigo, I. Gallego, J. Diez, and M. A. Fortuno Aldosterone Induces Cardiotrophin-1 Expression in HL-1 Adult Cardiomyocytes Endocrinology, October 1, 2008; 149(10): 4970 - 4978. [Abstract] [Full Text] [PDF]

				B. Lopez, J. M. Castellano, A. Gonzalez, J. Barba, and J. Diez Association of Increased Plasma Cardiotrophin-1 With Inappropriate Left Ventricular Mass in Essential Hypertension Hypertension, November 1, 2007; 50(5): 977 - 983. [Abstract] [Full Text] [PDF]

				T. Tsutamoto, S. Asai, T. Tanaka, H. Sakai, K. Nishiyama, M. Fujii, T. Yamamoto, M. Ohnishi, A. Wada, Y. Saito, et al. Plasma level of cardiotrophin-1 as a prognostic predictor in patients with chronic heart failure Eur J Heart Fail, October 1, 2007; 9(10): 1032 - 1037. [Abstract] [Full Text] [PDF]

				D. W. Ho, Z. F. Yang, C. K. Lau, K. H. Tam, J. Y. To, R. T. Poon, and S. T. Fan Therapeutic Potential of Cardiotrophin 1 in Fulminant Hepatic Failure: Dual Roles in Antiapoptosis and Cell Repair Arch Surg, November 1, 2006; 141(11): 1077 - 1084. [Abstract] [Full Text] [PDF]

				C. J. Pemberton, S. D. Raudsepp, T. G. Yandle, V. A. Cameron, and A. M. Richards Plasma cardiotrophin-1 is elevated in human hypertension and stimulated by ventricular stretch Cardiovasc Res, October 1, 2005; 68(1): 109 - 117. [Abstract] [Full Text] [PDF]

				O. Zolk, S. Engmann, F. Munzel, and R. Krajcik Chronic cardiotrophin-1 stimulation impairs contractile function in reconstituted heart tissue Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1214 - E1221. [Abstract] [Full Text] [PDF]

				J. G. Coles, C. Boscarino, M. Takahashi, D. Grant, A. Chang, J. Ritter, X. Dai, C. Du, G. Musso, H. Yamabi, et al. Cardioprotective stress response in the human fetal heart J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1128 - 1136. [Abstract] [Full Text] [PDF]

				D. H. Freed, R. H. Cunnington, A. L. Dangerfield, J. S. Sutton, and I. M.C. Dixon Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infarcted heart Cardiovasc Res, March 1, 2005; 65(4): 782 - 792. [Abstract] [Full Text] [PDF]

				X. Zheng, D. Zhou, C. Y. Seow, and T. R Bai Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1165 - L1171. [Abstract] [Full Text] [PDF]

				O. Zolk, F. Munzel, and T. Eschenhagen Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1248 - H1257. [Abstract] [Full Text] [PDF]

				A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez Cardiomyocyte apoptosis in hypertensive cardiomyopathy Cardiovasc Res, September 1, 2003; 59(3): 549 - 562. [Abstract] [Full Text] [PDF]

				Y. Nakaoka, K. Nishida, Y. Fujio, M. Izumi, K. Terai, Y. Oshima, S. Sugiyama, S. Matsuda, S. Koyasu, K. Yamauchi-Takihara, et al. Activation of gp130 Transduces Hypertrophic Signal Through Interaction of Scaffolding/Docking Protein Gab1 With Tyrosine Phosphatase SHP2 in Cardiomyocytes Circ. Res., August 8, 2003; 93(3): 221 - 229. [Abstract] [Full Text] [PDF]

				C. Ancey, E. Menet, P. Corbi, S. Fredj, M. Garcia, C. Rucker-Martin, J. Bescond, F. Morel, J. Wijdenes, J.-C. Lecron, et al. Human cardiomyocyte hypertrophy induced in vitro by gp130 stimulation Cardiovasc Res, July 1, 2003; 59(1): 78 - 85. [Abstract] [Full Text] [PDF]

				M. A. Fortuno, A. Gonzalez, S. Ravassa, B. Lopez, and J. Diez Clinical implications of apoptosis in hypertensive heart disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1495 - H1506. [Full Text] [PDF]

				E. K. Podewski, D. Hilfiker-Kleiner, A. Hilfiker, H. Morawietz, A. Lichtenberg, K. C. Wollert, and H. Drexler Alterations in Janus Kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) Signaling in Patients With End-Stage Dilated Cardiomyopathy Circulation, February 18, 2003; 107(6): 798 - 802. [Abstract] [Full Text] [PDF]

				M. R. Bristow and C. S. Long Cardiotrophin-1 in Heart Failure Circulation, September 17, 2002; 106(12): 1430 - 1432. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 106/12/1442    most recent 01.CIR.0000033117.39335.DFv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zolk, O. Articles by Eschenhagen, T. Search for Related Content PubMed PubMed Citation Articles by Zolk, O. Articles by Eschenhagen, T. Related Collections Congestive Growth factors/cytokines Related Article