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Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure.

Authors: Diedrichs, H  Chi, M  Boelck, B  Mehlhorn, U  Schwinger, RH 
Citation: Diedrichs H, etal., Eur J Heart Fail. 2004 Jan;6(1):3-9.
Pubmed: (View Article at PubMed) PMID:15012912
DOI: Full-text: DOI:10.1016/j.ejheart.2003.07.007

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 Ca(2+)-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 microl). 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)/microg 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/microg 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/microg protein). The protein expression of GATA-4 was increased in DCM (43.14+/-2.89 vs. 29.87+/-2.17 DU/microg 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.

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CRRD Object Information
CRRD ID: 1580709
Created: 2006-08-21
Species: All species
Last Modified: 2006-08-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.