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From the Department of Pharmacology,* Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, and the Departments of Pathology and Anesthesiology, Ernst-Moritz-Arndt-University, Greifswald; the Department of Cardiothoracic Surgery, Klinikum Karlsburg, Karlsburg; the Department of Cardiology, Saarland University, Homburg/Saar; the Dr. Margarete Fischer-Bosch-Institut fuer Klinische Pharmakologie,** Stuttgart; and Pharmacogenetics Laboratories,|| Epidauros Biotechnology, Bernried, Germany
The multidrug resistance protein 5 (MRP5/ABCC5) has been recently identified as cellular export pump for cyclic nucleotides with 3',5'-cyclic GMP (cGMP) as a high-affinity substrate. In view of the important role of cGMP for cardiovascular function, expression of this transport protein in human heart is of relevance. We analyzed the expression and localization of MRP5 in human heart [21 auricular (AS) and 15 left ventricular samples (LV) including 5 samples of dilated and ischemic cardiomyopathy]. Quantitative real-time polymerase chain reaction normalized to ß-actin revealed expression of the MRP5 gene in all samples (LV, 38.5 ± 12.9; AS, 12.7 ± 5.6; P < 0.001). An MRP5-specific polyclonal antibody detected a glycoprotein of 
190 kd in crude cell membrane fractions from these samples. Immunohistochemistry with the affinity-purified antibody revealed localization of MRP5 in cardiomyocytes as well as in cardiovascular endothelial and smooth muscle cells. Furthermore, we could detect MRP5 and ATP-dependent transport of [3H]cGMP in sarcolemma vesicles of human heart. Quantitative analysis of the immunoblots indicated an interindividual variability with a higher expression of MRP5 in the ischemic (104 ± 38% of recombinant MRP5 standard) compared to normal ventricular samples (53 ± 36%, P < 0.05). In addition, we screened genomic DNA from our samples for 20 single-nucleotide polymorphisms in the MRP5 gene. These results indicate that MRP5 is localized in cardiac and cardiovascular myocytes as well as endothelial cells with increased expression in ischemic cardiomyopathy. Therefore, MRP5-mediated cellular export may represent a novel, disease-dependent pathway for cGMP removal from cardiac cells.
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