Intermittent hypoxia protects cardiomyocytes against ischemia-reperfusion injury-induced alterations in Ca²⁺homeostasis and contraction via the sarcoplasmic reticulum and Na⁺/Ca²⁺exchange mechanisms

Abstract

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+)](i)). Because the sarcoplasmic reticulum (SR) and Na(+)/Ca(2+) exchanger (NCX) play crucial roles in regulating [Ca(2+)](i) 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+)](i) 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.

Berbamine Protects the Heart From Ischemia/Reperfusion Injury by Maintaining Cytosolic Ca²⁺ Homeostasis and Preventing Calpain Activation

“…3, 12 Freshly isolated adult rat cardiomyocytes were exposed to 20 min of simulated ischemia followed by 30 min reperfusion.…”

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion

“…contractile dysfunction (3,33), arrhythmias (31,52), and cell death (8,27). Recently, we (48) revealed a therapeutic effect of IHH on permanent coronary artery ligation-induced myocardial infarction by attenuating infarct size, myocardial fibrosis, and apoptosis and improving cardiac performance.…”

“…Recently, we (48) revealed a therapeutic effect of IHH on permanent coronary artery ligation-induced myocardial infarction by attenuating infarct size, myocardial fibrosis, and apoptosis and improving cardiac performance. Because IHH is a relatively simple intervention with a longer protection duration and fewer adverse effects and may offer profound benefit to patients with acute myocardial infarction (3,37), elucidating the mechanistic insights underlying the cardioprotective effects of IHH is critical to potential clinic applications.…”

Enhancement of Na/K pump activity by chronic intermittent hypobaric hypoxia protected against reperfusion injury

“…Our findings provide novel insights into the cellular and molecular mechanisms underlying the cardioprotection by CIHH against I/R-induced injury, which may help in the development of a preventive therapeutic regimen against ischemic injury. There are many researches about the mechanisms of CIHH-induced cardioprotection from I/R, such as upregulation of antioxidative enzymes (18), activation of ATPsensitive K ϩ channels (48), inhibition of mitochondrial permeability transition pores (49), changes in cardiac adrenergic receptors (17,41), alterations in sarco(endo)plasmic reticulum Ca 2ϩ -ATPase 2 (SERCA2) and the Na/Ca exchanger, ryanodine receptors, calmodulin kinase II, and activation of protein kinase C (PKC) (8,10,20). Certainly, like IPC, CIHH does not only involve one or two mechanisms in cardioprotective effects.…”

“…Nawada et al (28) proposed that IPC protects the rabbit heart against the I/Rinduced reduction in Na/K pump activity, and inhibition of Na/K pump activity has been shown to attenuate the beneficial effect of IPC. CIHH has been shown to attenuate [Na ϩ ] i and Ca 2ϩ overloaded during I/R (8,48). Therefore, prevention of Ca 2ϩ overload by CIHH may involve changes in Na/K pump activity.…”