© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischaemia and at reperfusion
aInstitute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK
bHatter Institute of Cardiology, University College Hospitals, London, UK
cDepartment of Protein Sciences, Genentech Inc., South San Francisco, CA, USA
dDepartment of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA
* Corresponding author. Tel.: +44-20-7905-2189; fax: +44-20-7242-8437 d.latchman{at}ich.ucl.ac.uk
Objectives: To determine whether the cytokine cardiotrophin-1 (CT-1) can protect the adult heart against ischaemia/reperfusion when added either prior to ischaemia or at reperfusion. Background: CT-1 has previously been shown to protect cultured embryonic or neonatal cardiocytes from cell death. To assess the therapeutic potential of CT-1, it is necessary to determine whether this effect can be observed in adult cardiac cells both in culture and most importantly in the intact heart. Methods: We examined the protective effect of CT-1 both in cultured adult rat cardiocytes and in the rat intact heart. In both cases, the cardiac cells were exposed to hypoxia/ischaemia followed by reoxygenation/reperfusion and CT-1 was administered either prior to hypoxia/ischaemia or at reoxygenation/reperfusion. Results: CT-1 has a protective effect in reducing ischaemic damage in the intact heart ex vivo as assayed by infarct size to area at risk ratio (20% compared to 35%). Similar protective effects against cell death were noted in adult cells in vitro. Both in vitro and ex vivo CT-1 can exert a protective effect when added at the time of reoxygenation/reperfusion as well as prior to the hypoxic/ischaemic stimulus (cell death reduced from 50 to 20% in TUNEL assay, infarct size to zone at risk ratio reduced from 35 to 20%). These protective effects are blocked by an inhibitor of the p42/p44 MAPK pathway. Conclusion: CT-1 can protect adult cardiac cells both in vitro and in vivo when added both prior to or after the hypoxic/ischaemic stimulus. The potential therapeutic benefit of CT-1 when added at the time of reperfusion following ischaemic damage is discussed.
Condensed abstract
The cytokine cardiotrophin-1 (CT-1) has previously been shown to have protective effects in embryonic or neonatal cardiac cells in culture. Here we show for the first time that CT-1 can protect adult cardiac cells both in culture and in the intact heart exposed to ischaemia/reperfusion. Moreover, this protective effect can be observed when CT-1 is added at reperfusion after ischaemia as well as prior to ischaemia. The ability of CT-1 to protect the intact adult heart when given at reperfusion suggests it may have therapeutic potential in the clinical situation.
KEYWORDS Apoptosis; Cytokines; Hypoxia/anoxia; Reperfusion
1 These authors contributed equally to the work.
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