Cardioprotection by intermittent high-altitude (IHA)
hypoxia against
ischemia-reperfusion (I/R) injury is associated with Ca(2+) overload reduction.
Phospholamban (PLB) phosphorylation relieves cardiac sarcoplasmic reticulum (SR) Ca(2+)-pump
ATPase, a critical regulator in intracellular Ca(2+) cycling, from inhibition. To test the hypothesis that IHA
hypoxia increases PLB phosphorylation and that such an effect plays a role in cardioprotection, we compared the time-dependent changes in the PLB phosphorylation at Ser(16) (PKA site) and Thr(17) (
CaMKII site) in perfused normoxic rat hearts with those in IHA hypoxic rat hearts submitted to 30-min
ischemia (I30) followed by 30-min reperfusion (R30). IHA
hypoxia improved postischemic contractile recovery, reduced the maximum extent of
ischemic contracture, and attenuated I/R-induced depression in Ca(2+)-pump
ATPase activity. Although the PLB
protein levels remained constant during I/R in both groups, Ser(16) phosphorylation increased at I30 and 1 min of reperfusion (R1) but decreased at R30 in normoxic hearts. IHA
hypoxia upregulated the increase further at I30 and R1. Thr(17) phosphorylation decreased at I30, R1, and R30 in normoxic hearts, but IHA
hypoxia attenuated the depression at R1 and R30. Moreover,
PKA inhibitor H89 abolished IHA
hypoxia-induced increase in Ser(16) phosphorylation, Ca(2+)-pump
ATPase activity, and the recovery of cardiac performance after
ischemia.
CaMKII inhibitor
KN-93 also abolished the beneficial effects of IHA
hypoxia on Thr(17) phosphorylation, Ca(2+)-pump
ATPase activity, and the postischemic contractile recovery. These findings indicate that IHA
hypoxia mitigates I/R-induced depression in SR Ca(2+)-pump
ATPase activity by upregulating dual-site PLB phosphorylation, which may consequently contribute to IHA
hypoxia-induced cardioprotection against I/R injury.