The cardioprotective effect persisting during recovery from cold acclimation is mediated by the beta(2)-adrenoceptor pathway and Akt activation
Abstrakt
The infarct size-limiting effect elicited by cold acclimation (CA) is accompanied by increased mitochondrial resistance and unaltered beta(1)-adrenergic receptor (AR) signaling persisting for 2 wk at room temperature. As the mechanism of CA-elicited cardioprotection is not fully understood, we examined the role of the salvage beta(2)-AR/G(i)/Akt pathway.
Male Wistar rats were exposed to CA (8 degrees C, 5 wk), whereas the recovery group (CAR) was kept at 24 degrees C for additional 2 wk. We show that the total number of myocardial beta-ARs in the left ventricular myocardium did not change after CA but decreased after CAR.
We confirmed the infarct size-limiting effect in both CA and CAR groups. Acute administration of beta(2)-AR inhibitor ICI-118551 abolished the protective effect in the CAR group but had no effect in the control and CA groups.
The inhibitory G(i)alpha(1/2) and G(i)alpha(3) proteins increased in the membrane fraction of the CAR group, and the phospho-Akt (Ser(473))-to-Akt ratio also increased. Expression, phosphorylation, and mitochondrial location of the Akt target glycogen synthase kinase (GSK-3 beta) were affected neither by CA nor by CAR.
However, GSK-3 beta translocated from the Z-disk to the H-zone after CA, and acquired its original location after CAR. Our data indicate that the cardioprotection observed after CAR is mediated by the beta 2-AR/G(i) pathway and Akt activation.
Further studies are needed to unravel downstream targets of the central regulators of the CA process and the downstream targets of the Akt protein after CAR. NEW & NOTEWORTHY Cardioprotective effect of cold acclimation and that persisting for 2 wk after recovery engage in different mechanisms.
The beta(2)-adrenoceptor/G(i) pathway and Akt are involved only in the mechanism of infarct size-limiting effect occurring during the recovery phase. GSK-3 beta translocated from the Z-line to the H-zone of sarcomeres by cold acclimation returns back to the original position after the recovery phase.
The results provide new insights potentially useful for the development of cardiac therapies.