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Published on: September 9, 2020
Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning
Robert M Smith1, Naushaad Suleman, Lydia Lacerda
1Hatter Institute for Cardiology Research, Faculty of Health Sciences, University of Cape Town Observatory, Cape Heart Centre, Chris Barnard Building, Cape Town 7925, South Africa. rsmith@sun.ac.za
Insights
Signal transducer and activator of transcription-3 (STAT-3) is not essential for basic cardiac myocyte survival during ischemia. However, STAT-3 is crucial for both ischemic and pharmacological preconditioning in the heart.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Signaling
Background:
- Ischemic heart disease remains a leading cause of mortality worldwide.
- Preconditioning strategies offer cardioprotection but their underlying molecular mechanisms require further elucidation.
- Signal transducer and activator of transcription-3 (STAT-3) is a key signaling molecule implicated in cellular responses to stress.
Purpose of the Study:
- To investigate the role of STAT-3 in cardiac myocyte tolerance to ischemia.
- To determine the necessity of STAT-3 for classical ischemic and pharmacological preconditioning in cardiomyocytes and the intact heart.
Main Methods:
- Cardiac myocyte-specific STAT-3 depletion was achieved in mice using Cre-lox technology.
- Cardiomyocyte viability was assessed after simulated ischemia (SI) with and without preconditioning.
- Langendorff heart preparations were used to evaluate infarct size following ischemia-reperfusion injury, with and without preconditioning.
Main Results:
- STAT-3 depletion did not affect basal cardiomyocyte viability following simulated ischemia.
- Both ischemic and pharmacological preconditioning failed to protect STAT-3-deficient cardiomyocytes.
- These findings were consistent in both isolated cardiomyocytes and whole-heart Langendorff preparations.
Conclusions:
- STAT-3 is dispensable for basal tolerance of cardiac myocytes to ischemic injury.
- STAT-3 is critically required for the cardioprotective effects of both ischemic and pharmacological preconditioning.
- Targeting STAT-3 may represent a novel therapeutic avenue for enhancing preconditioning-mediated cardioprotection.
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 microM adenosine, 100 microM diazoxide and 0.5 ng ml(-1) TNFalpha, 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.
