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Mechanisms of delayed electrical uncoupling induced by ischemic preconditioning
Sandeep K Jain1, Richard B Schuessler, Jeffrey E Saffitz
1Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Circulation Research
|May 6, 2003
Summary
Ischemic preconditioning delays cardiac myocyte uncoupling during ischemia by reducing connexin43 (Cx43) dephosphorylation and translocation. This protective effect involves KATP channels and protein kinase C (PKC).
Area of Science:
- Cardiology
- Cell Biology
- Physiology
Background:
- Ischemic preconditioning protects the heart against ischemia-reperfusion injury.
- Electrical uncoupling of cardiac myocytes limits arrhythmia substrate development during ischemia.
- Connexin43 (Cx43) plays a critical role in cardiac myocyte coupling.
Purpose of the Study:
- To investigate the mechanisms by which ischemic preconditioning delays electrical uncoupling of cardiac myocytes.
- To examine the role of connexin43 (Cx43) phosphorylation and subcellular distribution in this process.
Main Methods:
- Isolated, perfused rat hearts subjected to ischemic preconditioning protocol.
- Measurement of whole-tissue resistance to monitor electrical coupling.
- Quantitative immunoblotting and confocal microscopy to assess Cx43 phosphorylation and translocation.
- Pharmacological manipulation using KATP channel modulators and PKC inhibitors.
Main Results:
- Preconditioning reduced the rate of uncoupling by 34% and delayed its onset.
- Dephosphorylation and cytosolic translocation of Cx43 were significantly reduced in preconditioned hearts.
- KATP channel activation mimicked preconditioning effects, while inhibition blocked them.
- PKC inhibition prevented Cx43 translocation but not dephosphorylation.
Conclusions:
- Delayed uncoupling in preconditioned hearts is attributed to reduced Cx43 dephosphorylation and translocation.
- KATP channels are key regulators of these Cx43 modifications.
- PKC is involved in the internalization of Cx43 during ischemia.