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ATP-binding cassette transporters in human heart failure

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Abstract

Adenosine triphosphate-binding cassette (ABC) transporters are involved in energy-dependent transport of substrates across biological membranes. We hypothesized that their expression is altered during human heart failure, suggesting a pathophysiologic basis. Messenger ribonucleic acid quantification of all known ABC transporters revealed multiple alterations in ABC transporter expression in failing human hearts (New York Heart Association classification III–IV) compared to nonfailing controls. These include a loss of ABCC7 chloride channels and an increased expression of the KATP channel regulatory subunits ABCC8. Moreover, ABCG2, an efflux pump for xenobiotics/drugs, was expressed at much higher levels in failing hearts compared to nonfailing control hearts. ABCG2 was found in cardiac capillary endothelial cells and cardiomyocytes. Experiments in cells stably transfected with human ABCG2 revealed that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone was transported by ABCG2 but also inhibited the export of the prototypical ABCG2 substrate pheophorbide A (IC50 25 μM). These results suggest that altered ABC transporter expression in failing hearts might contribute to impaired channel conductance or might affect the cardiac disposition of drugs.

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Acknowledgments

Human tissue samples were generously provided by Matthias W. Beckmann (Head of the Department of Obstetrics and Gynecology, Erlangen University Hospital), Ingmar Blümcke (Head of the Department of Neuropathology, University of Erlangen-Nuremberg), and Thomas Papadopoulos (Acting Head of the Institute of Pathology, University of Erlangen-Nuremberg). This work was supported by the Deutsche Forschungsgemeinschaft (DFG FR 1298/2-4 and ZO 123/1-3) and the Johannes und Frieda Marohn Stiftung.

Ethical standards

The study complied with the principles outlined in the Declaration of Helsinki and was approved by our Institutional Ethics Committee. All subjects gave their informed consent prior to their inclusion in the study.

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstr. 17, 91054, Erlangen, Germany

    Thomas F. Solbach, Barbara Paulus, Oliver Zolk & Martin F. Fromm

  2. Center of Cardiac Surgery, University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054, Erlangen, Germany

    Michael Weyand

  3. Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Thomas Eschenhagen

Authors
  1. Thomas F. Solbach
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  2. Barbara Paulus
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  3. Michael Weyand
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  4. Thomas Eschenhagen
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  5. Oliver Zolk
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  6. Martin F. Fromm
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Corresponding author

Correspondence to Oliver Zolk.

Additional information

B.P. and T.F.S. contributed equally.

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Electronic Supplementary Material Table 1

Primer sequences (DOC 109 KB)

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Solbach, T.F., Paulus, B., Weyand, M. et al. ATP-binding cassette transporters in human heart failure. Naunyn-Schmied Arch Pharmacol 377, 231–243 (2008). https://doi.org/10.1007/s00210-008-0279-6

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  • DOI: https://doi.org/10.1007/s00210-008-0279-6

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