© 2004 European Society of Cardiology
Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure
a Laboratory of Muscle Research and Molecular Cardiology University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany
b Department of Cardiothoracic Surgery University of Cologne, Cologne, Germany
* Corresponding author. Tel.: +49-221-478-6205; fax: +49-221-478-6550. E-mail address: robert.schwinger{at}medizin.uni-koeln.de
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Abstract |
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Background: Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca2+-calmodulin activated phosphatase calcineurin and its downstream transcriptional effector NFAT have been implicated as transducers of the hypertrophic response.
Methods and results: To study whether the calcineurin pathway is activated in human heart failure, we investigated samples of human left ventricular myocardium from patients with dilated (idiopathic) cardiomyopathy (DCM, NYHA IV, n=8) in comparison with non-failing controls (NF, n=8). We not only analyzed the pathway by measuring the calcineurin activity, but also by determination of the protein expression of the calcineurin B subunit and additional key markers of the calcineurin signaling cascade (NFAT-3, GATA-4). Calcineurin enzymatic activity was increased by 80% in human dilated cardiomyopathy compared with non-failing human hearts (135.424±11.69 and 83.484±1.81 nmol Pi/min per µl). This was in line with increased protein expression of calcineurin B in DCM (71.18+9.11 vs. 46.41±11.23 densitometric units (DU)/µg protein). In order to verify the activated calcineurin pathway as described in animal models, we compared the protein expression of NFAT-3 in homogenates within nuclear extracts. In nuclear extracts the protein level of NFAT-3 was increased in dilated cardiomyopathy compared with non-failing myocardium (104.01±8.85 vs. 71.47±8.79 DU/µg protein). In contrast, in homogenates the expression of NFAT-3 was higher in the non-failing tissue indicating subcellular redistribution (19.56±3.36 vs. 25.84±3.16 DU/µg protein). The protein expression of GATA-4 was increased in DCM (43.14±2.89 vs. 29.87±2.17 DU/µg protein).
Conclusions: In human heart failure (DCM) the calcineurin signaling pathway is activated not only by an increased activity of calcineurin and expression of GATA-4, but also by the shift from dephosphorylated NFAT-3 to the nucleus indicating subcellular redistribution and regulatory activation.
Key Words: Calcineurin • NFAT-3 • GATA-4 • Cardiomyopathy • Hypertrophy • Heart failure
Received May 26, 2003; Revised July 1, 2003; Accepted July 8, 2003
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