CLINICAL RESEARCH: CARDIOMYOPATHY
Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy
Björn Szotowski, MPharm*, ,
Petra Goldin-Lang, PhD*,
Silvio Antoniak, MS*,
Vladimir Y. Bogdanov, PhD ,
Delano Pathirana*,
Matthias Pauschinger, MD*,
Andrea Dörner, PhD*,
Uwe Kuehl, PhD*,
Sarah Coupland, MD ,
Yale Nemerson, MD,
Michael Hummel, MD,
Wolfgang Poller, MD*,
Roland Hetzer, MD, PhD||,
Heinz-Peter Schultheiss, MD* and
Ursula Rauch, MD*,*
* Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
Institute of Pharmacy, Free University of Berlin, Berlin, Germany
Department of Medicine, Mount Sinai School of Medicine, New York, New York
Institute of Pathology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
|| Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
Manuscript received September 13, 2004;
revised manuscript received November 29, 2004,
accepted December 6, 2004.
* Reprint requests and correspondence: Dr. Ursula Rauch, Medical Clinic II, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
(Email: ursula.rauch{at}charite.de).
OBJECTIVES: We investigated the myocardial localization and expression of tissue factor (TF) and alternatively spliced human tissue factor (asHTF) in patients with dilated cardiomyopathy (DCM).
BACKGROUND: Tissue factor is expressed in cardiac muscle and may play a role in maintaining myocardial structure.
METHODS: Myocardial biopsies were obtained from patients with a normal or mildly impaired ejection fraction (EF) ( 50%) and moderate to severely reduced EF (<50%). Explanted DCM hearts were also examined. Myocardial TF expression level was assessed by real-time polymerase chain reaction, TF protein by enzyme-linked immunosorbent assay, and localization by immunohistochemistry.
RESULTS: We report the identification of asHTF in the human myocardium: it was located in cardiomyocytes and endothelial cells. Quantification of myocardial TF messenger ribonucleic acid in DCM revealed a decrease in the TF/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratio (1.76 x 10–1 ± 6.08 x 10–2 for EF 50% [n = 19] vs. 1.06 x 10–1 ± 5.26 x 10–2 for EF <50% [n = 27]; p < 0.001) and asHTF/GAPDH ratio (13.91 x 10–5 ± 11.20 x 10–5 for EF 50% vs. 7.17 x 10–5 ± 3.82 x 10–5 for EF <50%; p = 0.014). Tissue factor isoform expression level was also decreased in explanted DCM hearts (p < 0.01; n = 12). Total TF protein was reduced by 26% in DCM (p < 0.05). The TF/GAPDH ratio correlated positively with the EF (r = 0.504, p < 0.0001). Immunohistochemistry showed TF localized to the sarcolemma and Z-bands of the cardiomyocytes in patients with normal EF, whereas TF was found in the cardiomyocytic cytosol around the nucleus in DCM.
CONCLUSIONS: Tissue factor was down-regulated in the myocardium of DCM patients. The reduction in TF expression and change in localization may influence cell-to-cell contact stability and contractility, thereby contributing to cardiac dysfunction in DCM.
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Abbreviations and Acronyms
| | ACE = angiotensin-converting enzyme | | asHTF = alternatively spliced human tissue factor | | DCM = dilated cardiomyopathy | | DNA = deoxyribonucleic acid | | EF = ejection fraction | | ELISA = enzyme-linked immunosorbent assay | | mRNA = messenger ribonucleic acid | | PCR = polymerase chain reaction | | TF = tissue factor |
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