Published Online
on February 3, 2003

A more recent version of this article appeared on February 18, 2003

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Submitted on November 7, 2002
Revised on December 20, 2002
Accepted on January 3, 2003

Alterations in Janus Kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) Signaling in Patients With End-Stage Dilated Cardiomyopathy

Edith K. Podewski MD, Denise Hilfiker-Kleiner PhD, Andres Hilfiker PhD, Henning Morawietz PhD, Artur Lichtenberg MD, Kai C. Wollert MD, and Helmut Drexler MD^*

From the Departments of Cardiology and Angiology (E.K.P., D.H.K., A.H., K.C.W., H.D.), and Cardiovascular Surgery (A.L.), Hannover Medical School, Hannover, Germany, and the Institute of Pathophysiology (H.M.), University of Halle-Wittenberg, Germany.

^* To whom correspondence should be addressed. E-mail: drexler.helmut{at}mh-hannover.de.

Background--Experimental studies indicate that interleukin-6 (IL-6)-related cytokines, signaling via the shared receptor gp130, Janus kinases (JAKs), and signal transducers and activators of transcription (STATs), provide a critical cardiomyocyte survival pathway in vivo. Little is known about the activation of this signaling pathway in the myocardia of patients with end-stage dilated cardiomyopathy (DCM).

Methods and Results--We performed a comprehensive expression and activation analysis of IL-6-related cytokines, receptors, signal transducers, and signal transduction inhibitors in left ventricular (LV) myocardia from patients with DCM (n=10) and non-failing (NF) donor hearts (n=5). Differential expression (DCM versus NF) was observed by immunoblotting at each level of the signaling cascade, including receptor ligands (IL-6: -59%, P<0.01; leukemia inhibitory factor [LIF]: +54%, P<0.05), receptor subunits (LIF receptor: -16%, P<0.05), signaling molecules (the Janus kinase TYK2: -48%, P<0.01; STAT3: -47%, P<0.01), and suppressors of cytokine signaling (SOCS1: +97%, P<0.05; SOCS3: -49%, P<0.01). Tyrosine-phosphorylation status of gp130 was increased (+60%, P<0.05), whereas tyrosine-phosphorylation status of JAK2 was reduced in DCM (-72%, P<0.01). Moreover, as shown by immunohistochemistry, the number of STAT3-positive cardiomyocytes was reduced in DCM (-42%, P<0.01).

Conclusion--Signaling via gp130 and JAK-STAT is profoundly altered in DCM. Importantly, tyrosine-phosphorylation of JAK2 is reduced in the face of increased gp130 phosphorylation, indicating impaired downstream activation of this critical pathway in DCM.

Key words: cardiomyopathy • interleukins • signal transduction

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