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首页> 外文期刊>American Journal of Physiology >Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury.
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Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury.

机译：双位磷酸lambanban磷酸化在间歇性缺氧诱导的抗缺血再灌注损伤的心脏保护作用。

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摘要

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.
机译：间歇性高海拔（IHA）缺氧对缺血再灌注（I / R）损伤的心脏保护作用与Ca（2+）超负荷减少相关。 Phospholamban（PLB）磷酸化解除抑制的心肌肌浆网（SR）Ca（2 +）-泵ATPase，在细胞内Ca（2+）循环中的关键调节剂。为了测试IHA缺氧会增加PLB磷酸化以及这种作用在心脏保护中起作用的假设，我们比较了Ser（16）（PKA位点）和Thr（17）（CaMKII位点）PLB磷酸化的时间依赖性变化在正常氧灌流大鼠心脏中进行的IHA缺氧大鼠心脏缺血30分钟（I30），然后再进行30分钟再灌注（R30）。 IHA缺氧改善缺血后的收缩恢复，减少最大程度的缺血性挛缩，并减弱I / R诱导的Ca（2 +）-泵ATPase活性降低。尽管两组的PL蛋白质水平在I / R期间均保持不变，但在常氧性心脏中，Ser（16）磷酸化在I30和再灌注（R1）1分钟时增加，但在R30时降低。 IHA低氧进一步上调了I30和R1处的升高。在常氧性心脏中，I30，R1和R30处的Thr（17）磷酸化降低，但是IHA低氧减轻了R1和R30处的抑郁。此外，PKA抑制剂H89消除了IHA低氧诱导的Ser（16）磷酸化，Ca（2 +）-泵ATPase活性的增加以及缺血后心脏功能的恢复。 CaMKII抑制剂KN-93还取消了IHA低氧对Thr（17）磷酸化，Ca（2 +）-泵ATPase活性和缺血后收缩恢复的有益作用。这些发现表明，IHA低氧通过上调双位点PLB磷酸化来减轻I / R诱导的SR Ca（2 +）-泵ATPase活性降低，因此可能有助于IHA低氧诱导的针对I / R损伤的心脏保护。

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