Na⁺/Ca²⁺ exchanger plays a key role in inducing apoptosis after hypoxia in cultured guinea pig ventricular myocytes

Abstract

Altered Na(+)/Ca(2+) exchanger (NCX) protein expression or activity is thought to contribute to various aspects of cardiac pathology. In guinea pig ventricular myocytes, NCX-mediated Ca(2+) entry is almost entirely responsible for Ca(2+) overload during hypoxia-reoxygenation. Because Ca(2+) overload is a common initiator of apoptosis, the purpose of this study was to test the hypotheses that NCX activity is critically involved in initiating apoptosis after hypoxia-reoxygenation and that hypoxia-reoxygenation-induced apoptosis can be modulated by changes in NCX protein expression or activity. An NCX antisense oligonucleotide was used to reduce NCX protein expression in cultured adult guinea pig ventricular myocytes. Caspase-3 activation and cytochrome c release were used as markers of apoptosis. Hypoxia-reoxygenation-induced apoptosis was significantly decreased in antisense-treated myocytes compared with untreated control or nonsense-treated myocytes. Pretreatment of cultured myocytes for 24 h with either endothelin-1 or phenylephrine was found to increase both NCX protein expression and evoked NCX activity as well as enhance hypoxia-reoxygenation-induced apoptosis. Control experiments demonstrated that endothelin-1 and phenylephrine did not induce apoptosis on their own nor did they enhance the apoptotic response in a model of Ca(2+)-dependent, NCX-independent apoptosis. Additional control experiments demonstrated that the NCX antisense oligonucleotide did not alter the apoptotic response of myocytes to either H(2)O(2) or isoproterenol. Taken together, these data suggest that the NCX has a critical and specific role in the initiation of apoptosis after hypoxia-reoxygenation in guinea pig myocytes and that hypoxia-reoxygenation-induced apoptosis is quite sensitive to changes in NCX activity.

CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia–reperfusion injury

“…The involvement of the NCX, both in forward and reverse modes, in the production of SR Ca 2+ overload and apoptosis has been also previously reported [27,28]. The present results confirm these findings, since the deleterious effect of reperfusion was abolished in isolated myocytes by blocking the reverse NCX mode with the specific inhibitor KBR.…”

Propofol administration to the fetal–maternal unit reduces cardiac injury in late-preterm lambs subjected to severe prenatal asphyxia and cardiac arrest

“…Another pathway that contributes to myocardial protection in ischemic postconditioning is activation of 26). A recent study by Bolli et al has provided evidence that recruitment of STAT3 plays an essential role in the upregulation of cardioprotective and antiapoptotic proteins; the evidence further suggests that STAT3 activation is important in inhibiting both the death receptor pathway and the mitochondrial pathway (27).…”

“…Some previous studies have demonstrated that the level of phosphorylated AKT may reflect its activity under conditions such as preconditioning (24) and postconditioning (23). Therefore, the findings of our study suggest that propofol administration to the mother and to the fetus at the onset of reperfusion for 8 h might attenuate myocardial apoptosis, partly through maintaining or even increasing the activity of the phosphoinositide-3-kinase/AKT pathway.Another pathway that contributes to myocardial protection in ischemic postconditioning is activation of 26). A recent study by Bolli et al has provided evidence that recruitment of STAT3 plays an essential role in the upregulation of cardioprotective and antiapoptotic proteins; the evidence further suggests that STAT3 activation is important in inhibiting both the death receptor pathway and the mitochondrial pathway (27).…”

Androstenediol inhibits the trauma-hemorrhage-induced increase in caspase-3 by downregulating the inducible nitric oxide synthase pathway

“…It has been shown that caspase-3 activity is increased by hypoxia (12,25), ischemia (10,36,53), hemorrhage (9,22,26,29,32,33,60), and in other pathological conditions (1,33,34,39,46,52). Interventions that lead to inhibition of caspase-3 activity (60), such as treadmill exercise (26), hypertonic saline resuscitation (33), or LR resuscitation (23), have been shown to reduce tissue apoptosis and brain damage in hemorrhaged animals.…”