Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning
Open Access
- 1 February 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 296 (2), H396-H403
- https://doi.org/10.1152/ajpheart.00448.2008
Abstract
Ischemic preconditioning (PC) suppresses chemical coupling of cardiomyocytes via gap junctions (GJs) during ischemia, which is an adjunct mechanism of protection. The aim of this study was to characterize roles of protein kinases in PC-induced GJ modulation. In isolated rat hearts, ventricular tissues were sampled before and after ischemia with or without PC, and intercalated disc-rich fractions were separated for immunoprecipitation and immunoblotting. Levels of protein kinase C (PKC)-ε, p38mitogen-activated protein kinase (MAPK)-α, and Src coimmunoprecipitated with connexin-43 (Cx43) were increased after ischemia, whereas p38MAPKβ was not detected in the Cx43 immunoprecipitates. PC did not modify the level of Cx43-Src complex after ischemia. However, PC enhanced Cx43-PKCε complex formation, which was abolished by PKCε translocation inhibitory peptide (TIP). In contrast, PC reduced Cx43-p38MAPKα complex level and p38MAPK activity in the Cx43 immunoprecipitates after ischemia. The effect of PC on Cx43-p38MAPKα interaction was mimicked by SB-203580, a p38MAPK inhibitor. PC reduced permeability of GJs to Lucifer yellow in the myocardium at 25 min after ischemia, and this effect was abolished by PKCε-TIP. SB-203580 increased the GJ permeability at 15 min after ischemia compared with that in untreated controls, but the difference became insignificant 25 min after ischemia. In conclusion, PC has distinct effects on interaction of GJ Cx43 with PKCε, p38MAPKα, and Src during ischemia. Suppression of GJ permeability during ischemia by PC is primarily achieved by enhanced interaction of Cx43 with PKCε, which overwhelms the counterbalancing effect of reduced Cx43-p38MAPKα interaction.Keywords
This publication has 32 references indexed in Scilit:
- δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-ε-mediated phosphorylation of connexin 43American Journal of Physiology-Heart and Circulatory Physiology, 2007
- Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathwaysJournal of Molecular and Cellular Cardiology, 2007
- Protective effect of gap junction uncouplers given during hypoxia against reoxygenation injury in isolated rat heartsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2006
- Regulation of Connexin43-Protein Binding in Astrocytes in Response to Chemical Ischemia/HypoxiaJournal of Biological Chemistry, 2005
- Anisomycin downregulates gap-junctional intercellular communication via the p38 MAP-kinase pathwayJournal of Cell Science, 2004
- p38/SAPK2 controls gap junction closure in astrocytesGlia, 2004
- Protein kinase activation and myocardial ischemia/reperfusion injuryCardiovascular Research, 2004
- Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivoThe FASEB Journal, 2003
- The role of p38 mitogen-activated protein kinase in myocardial ischemia/reperfusion injury; relationship to ischemic preconditioningBasic Research in Cardiology, 2002
- Role of Kinins in the Cardioprotective Effect of PreconditioningHypertension, 1997