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Eur J Cardiothorac Surg 2003;23:984-990
© 2003 Elsevier Science NL

Cardioplegic arrest induces apoptosis signal-pathway in myocardial endothelial cells and cardiac myocytes

Uwe M. Fischera, Oliver Klassa, Ulrike Stockb, Jerry Easoa, Hans J. Geisslera, Juergen H. Fischerc, Wilhelm Blochb, Uwe Mehlhorna*

a Department of Cardiothoracic Surgery1, University of Cologne, Cologne, Germany
b Institute I for Anatomy2, University of Cologne, Cologne, Germany
c Institute for Experimental Medicine3, University of Cologne, Cologne, Germany

Received 10 September 2002; received in revised form 29 January 2003; accepted 17 February 2003.

* Corresponding author. Tel.: +49-221-478-6043; fax: +49-221-478-5906
e-mail: uwe.mehlhorn{at}medizin.uni-koeln.de

Objective: Myocardial ischemia–reperfusion is associated with free radical-mediated injury and may be involved in cardiac apoptosis. The purpose of our study was to investigate (1) if cardioplegia-induced ischemia–reperfusion initiates cardiac apoptosis signal pathway, and (2) if this is mediated by free radicals. Methods: We subjected 13 pigs (56±10 kg) to 1 h of cold crystalloid cardioplegic arrest (CA) on cardiopulmonary bypass (CPB), and collected five transmural LV biopsies: prior to CPB (baseline), at 60 min CA, at 15 and 30 min reperfusion on CPB, and at 120 min post CPB. Two additional pigs were subjected to CPB but not CA and two further pigs were neither subjected to CPB nor CA and served as sham-operated time controls. LV specimens were cut at 7 µm and immunocytochemically stained against active caspase-3 and 85 kDa poly(ADP-ribose) polymerase (PARP) as apoptosis signal-pathway key enzymes, nitrotyrosine as indicator for peroxynitrite (ONOO-)-mediated tissue injury, and 8-iso-prostaglandin-F2{alpha} as indicator for oxygen free radical-mediated lipid peroxidation. Specimen were assessed using a scale of 0 (negative) to 3 (highly positive), and cardiomyocytes were quantitatively investigated using TV densitometry. Results: At 60 min CA, caspase-3 was increased by 9.2±3.7 gray units and remained on this level until 2 h post CPB (P≤0.003 vs. baseline); nitrotyrosine increased over time to reach a maximum of +8.5±8.1 gray units at 120 min post CPB (P=0.016); and there was a trend for increased 8-iso-prostaglandin-F2{alpha} at 60 min CA (+3.6±4.7 gray units; P=0.089). At 60 min CA, 92% of the hearts showed active caspase-3, only 42% demonstrated nitrotyrosine formation, and 58% exhibited 8-iso-prostaglandin-F2{alpha}. At 120 min post CPB, most hearts positive for caspase-3 were also positive for nitrotyrosine (83%), and 8-iso-prostaglandin-F2{alpha} (75%), but no heart showed PARP cleavage. Hearts subjected to CPB but not CA as well as time controls remained negative for all variables. Conclusions: Our data show that CA initiates apoptosis signal-pathway in myocardial endothelium and myocytes; however, this did not result in apoptotic cell death as we did not find PARP cleavage. Further, the data suggest that CA-induced apoptosis signal pathway activation is not mediated by free radicals as caspase-3 activation preceded both nitrotyrosine and 8-iso-prostaglandin-F2{alpha} formation.

Key Words: Apoptosis signal pathway • Caspase-3 • Poly(ADP-ribose) polymerase • Nitrotyrosine • 8-Iso-prostaglandin-F2{alpha} • Ischemia • Reperfusion • Cardiopulmonary bypass • Cardioplegia




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