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CLINICAL STUDY: HEART FAILURE

Deoxyribonucleic acid damage/repairproteins are elevated in the failing human myocardium due to idiopathic dilated cardiomyopathy

Jozef Bartunek, MD, PhD^*,*, Marc Vanderheyden, MD, Michiel W. M. Knaapen, PhD, Wouter Tack, RSN^*, Mark M. Kockx, MD, PhD and Marc Goethals, MD^*

^* Cardiovascular Center, Aalst, Belgium
Department of Cardiology, Imelda Ziekenhuis, Bonheiden, Belgium
HistoGeneX, Edegem, Belgium
Department of Pathology, Middelheim Hospital, Antwerp, Belgium

Manuscript received November 26, 2001; revised manuscript received April 11, 2002, accepted June 18, 2002.

^* Reprint requests and correspondence: Dr. Jozef Bartunek, Cardiovascular Center, OLV Ziekenhuis, Moorselbaan 164, 9 300 Aalst, Belgium.
jozef.bartunek{at}olvz-aalst.be

OBJECTIVES: The study investigated the expression and relationship of deoxyribonucleic acid (DNA) repair enzymes with hemodynamic and nitric oxide (NO)-mediated stress in the failing myocardium.

BACKGROUND: The role of apoptosis in human heart failure is controversial. Experimental studies suggested that NO-mediated stress modulates apoptosis of the cardiac myocytes. Of note, DNA repair enzymes such as redox factor/apurinic/apyridimine endonuclease Ref-1 protein, proliferative cell nuclear antigen (PCNA), the poly (ADP-ribose) polymerase (PARP), and DNA-protein kinase (DNA-PK) determine the cell fate after the DNA damage.

METHODS: Left ventricular (LV) endomyocardial biopsies from 23 patients with dilated cardiomyopathy were analyzed by immunohistochemistry.

RESULTS: Terminal deoxynucleotidyltransferase-mediated biotin-dUTP nick-end labeling (TUNEL) or cleaved caspase-3 and cleaved PARP could not be detected. The number of Ref-1-positive myocytes tended to be higher in patients with LV ejection fraction (EF) 35% versus LV EF >35% (21.23 ± 4.8% vs. 13.8 ± 5.8%, p = 0.1). The PCNA (7.1 ± 2.8% vs. 0.9 ± 0.6%, p = 0.05) and DNA-PK expressions (39.5 ± 5.4% vs. 8.6 ± 5.5%, p < 0.01) were higher in patients with LVEF 35% vs. LVEF >35%. The PCNA, Ref-1, and DNA-PK expression correlated with the LV end-systolic wall stress (r = 0.61, p < 0.01; r = 0.52, p < 0.01; and r = 0.73, p < 0.001, respectively). In addition, the PCNA and DNA-PK expression correlated with inducible NO synthase (r = 0.41, p = 0.05, and r = 0.53, p < 0.01, respectively).

CONCLUSIONS: In this study, apoptosis could not be detected in the failing myocardium owing to idiopathic dilated cardiomyopathy. In contrast, failing myocardium was characterized by active DNA repair that was associated with elevated LV wall stress and activation of the inducible NO synthase.

Abbreviations and Acronyms   APE/Ref-1   redox factor apurinic/apyrimidine endonuclease Ref-1 protein   DNA   deoxyribonucleic acid   DNA-PKcs   deoxyribonucleic acid-protein kinase catalytic subunit   iNOS   inducible nitric oxide synthase   LV   left ventricle/ventricular   LVEF   left ventricular ejection fraction   PARP   poly (adenosine diphosphate-ribose) polymerase   PCNA   proliferative cell nuclear antigen   RNA   ribonucleic acid   TUNEL   terminal deoxynucleotidyltranseferase-medaited biotin-dUTP nick-end labeling

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