Abstract 13020: Induced Connexin43 Knock-Out Impairs Myocardial Energetic Metabolism, Increases Tolerance to Ischemia-Reperfusion and Abolishes Preconditioning Protection
Replacement of connexin43 (Cx43) by Cx32 in Cx43KI32 mice alters energetic metabolism, increases tolerance to ischemia-reperfusion injury and abolishes preconditioning protection. However, it has not been excluded that these effects are due to secondary changes in gene expression or to the presence of Cx32. Here, we analyzed the effects of an extreme, acute, reduction in the number of gap junction channels after 4-hydroxytamoxifen (4-OHT) treatment in Cx43Cre-ER(T)/fl mice on energetic metabolism, tolerance to ischemia-reperfusion injury and preconditioning protection.
Methods and Results. Treatment with 4-OHT in Cx43Cre-ER(T)/fl mice markedly reduces Cx43 expression to less than 5% of that seen in Cx43fl/fl animals treated with vehicle. Isolated, Langendorff-perfused, hearts from Cx43Cre-ER(T)/fl mice treated with 4-OHT showed an increased tolerance to ischemia (40 min)-reperfusion (60 min) injury compared with remaining groups (p<0.01, n=8-9/group) (see figure), whereas protection by pharmacological preconditioning with diazoxide (Dzx., 50 µM, 10 min), but not by ischemic preconditioning (IPC, four cycles of ischemia (3.5 min) and reperfusion (5 min)) was abolished in Cx43Cre-ER(T)/fl mice treated with vehicle (see figure). 31P-NMR spectroscopy of Langendorff-perfused mice hearts showed a reduction in PCr/ATP ratio after marked Cx43 gene deletion with 4-OHT (Cx43Cre-ER(T)/fl + 4-OHT: 0.78±0.06 vs 1.61±0.15 in Cx43fl/fl + vehicle, p<0.05, n=4).
Conclusions. A marked reduction in Cx43 expression alters myocardial energetic metabolism and increases tolerance to ischemia-reperfusion injury. A milder decrease in Cx43 expression is associated with loss of preconditioning protection induced by diazoxide. These data demonstrate that Cx43 has important, isoform specific, functions beyond gap junctional communication.
- © 2011 by American Heart Association, Inc.