© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning
aHatter Institute for Cardiology Research, Faculty of Health Sciences, University of Cape Town Observatory, Cape Heart Centre, Chris Barnard Building, Cape Town 7925, South Africa
bResearch Institute for Microbial Diseases, Osaka University, Osaka, Japan
cInstitute of Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
dNational Institute of Health, National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, MD, USA
* Corresponding author. Tel.: +27 21 808 3154; fax: +27 21 808 3145. Email address: rsmith{at}sun.ac.za
Objective: To evaluate the functional requirement of signal transducer and activator of transcription-3 (STAT-3) in cardiac myocyte tolerance to ischemia (I) and in classical preconditioning.
Methods: Cardiac myocyte STAT-3 was depleted in mice using Cre–lox p technology. Isolated cardiomyocytes from wild-type (WT) and STAT-3-deficient mice were evaluated for viability following simulated ischemia (SI; 26 h). Cardiomyocytes were then preconditioned by exposure to transient simulated ischemia or via the administration of preconditioning mimetics (100 µM adenosine, 100 µM diazoxide and 0.5 ng ml–1 TNF
, individually and in combination) prior to index ischemia. To evaluate the effect of cardiac myocyte depletion of STAT-3 in the context of the intact heart, these experiments were performed in isolated perfused Langendorff heart preparations which were exposed to an index insult of 30-min global ischemia and 45-min reperfusion. Ischemic preconditioning was achieved by subjecting the hearts to four cycles of 5-min ischemia followed by 5-min reperfusion prior to index ischemia. Infarct size was measured following reperfusion.
Results: Cell viability was diminished equally in wild-type and STAT-3-depleted cardiomyocytes. In contrast, ischemic and pharmacological preconditioning protected wild-type cardiomyocytes but not STAT-3-deficient cardiomyocytes. These results were mirrored in the intact heart.
Conclusion: The depletion of functional STAT-3 does not modulate tolerance to ischemic injury in cardiomyocytes. This signaling molecule, however, is crucial for the ischemic and all the tested pharmacological preconditioning programs.
KEYWORDS Ischemia; Preconditioning; Signal transduction
1 From 1st July 2004, Department of Physiological Sciences, University of Stellenbosch, Private Bag X1, Matieland, 7602 South Africa. Tel.: +27 21 808 3146; fax: +27 21 808 3145.
Time for primary review 5 days
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