Chen Le, Lu Xi-Yuan, Li Jun, Fu Ji-Dong, Zhou Zhao-Nian, Yang Huang-Tian
Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, 225 Chong Qing Nan Rd., #1 Bldg., Shanghai 200025, China.
Am J Physiol Cell Physiol. 2006 Apr;290(4):C1221-9. doi: 10.1152/ajpcell.00526.2005. Epub 2005 Nov 23.
We have previously demonstrated that intermittent high-altitude (IHA) hypoxia significantly attenuates ischemia-reperfusion (I/R) injury-induced excessive increase in resting intracellular Ca(2+) concentrations (Ca(2+)). Because the sarcoplasmic reticulum (SR) and Na(+)/Ca(2+) exchanger (NCX) play crucial roles in regulating Ca(2+) and both are dysfunctional during I/R, we tested the hypothesis that IHA hypoxia may prevent I/R-induced Ca(2+) overload by maintaining Ca(2+) homeostasis via SR and NCX mechanisms. We thus determined the dynamics of Ca(2+) transients and cell shortening during preischemia and I/R injury in ventricular cardiomyocytes from normoxic and IHA hypoxic rats. IHA hypoxia did not affect the preischemic dynamics of Ca(2+) transients and cell shortening, but it significantly suppressed the I/R-induced increase in resting Ca(2+) levels and attenuated the depression of the Ca(2+) transients and cell shortening during reperfusion. Moreover, IHA hypoxia significantly attenuated I/R-induced depression of the protein contents of SR Ca(2+) release channels and/or ryanodine receptors (RyRs) and SR Ca(2+) pump ATPase (SERCA2) and SR Ca(2+) release and uptake. In addition, a delayed decay rate time constant of Ca(2+) transients and cell shortening of Ca(2+) transients observed during ischemia was accompanied by markedly inhibited NCX currents, which were prevented by IHA hypoxia. These findings indicate that IHA hypoxia may preserve Ca(2+) homeostasis and contraction by preserving RyRs and SERCA2 proteins as well as NCX activity during I/R.
我们先前已经证明，间歇性高海拔（IHA）缺氧可显著减轻缺血再灌注（I/R）损伤诱导的静息细胞内Ca(2+)浓度（Ca(2+)）过度升高。由于肌浆网（SR）和钠钙交换体（NCX）在调节Ca(2+)方面起关键作用，且二者在I/R期间均功能失调，我们检验了这样一个假设，即IHA缺氧可能通过SR和NCX机制维持Ca(2+)稳态，从而防止I/R诱导的Ca(2+)超载。因此，我们测定了常氧和IHA缺氧大鼠心室心肌细胞在缺血前及I/R损伤期间Ca(2+)瞬变和细胞缩短的动态变化。IHA缺氧不影响缺血前Ca(2+)瞬变和细胞缩短的动态变化，但它显著抑制了I/R诱导的静息Ca(2+)水平升高，并减轻了再灌注期间Ca(2+)瞬变和细胞缩短的降低。此外，IHA缺氧显著减轻了I/R诱导的SR Ca(2+)释放通道和/或兰尼碱受体（RyRs）以及SR Ca(2+)泵ATP酶（SERCA2）的蛋白含量降低，以及SR Ca(2+)的释放和摄取。另外，缺血期间观察到的Ca(2+)瞬变延迟衰减速率时间常数和Ca(2+)瞬变的细胞缩短伴随着NCX电流的明显抑制，而IHA缺氧可防止这种抑制。这些发现表明，IHA缺氧可能通过在I/R期间保留RyRs和SERCA2蛋白以及NCX活性来维持Ca(2+)稳态和收缩功能。
