Chronic intermittent hypoxia alters Ca²⁺ handling in rat cardiomyocytes by augmented Na⁺/Ca²⁺ exchange and ryanodine receptor activities in ischemia-reperfusion

Abstract

This study examined Ca(2+) handling mechanisms involved in cardioprotection induced by chronic intermittent hypoxia (CIH) against ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were exposed to 10% inspired O(2) continuously for 6 h daily from 3, 7, and 14 days. In isolated perfused hearts subjected to I/R, CIH-induced cardioprotection was most significant in the 7-day group with less infarct size and lactate dehydrogenase release, compared with the normoxic group. The I/R-induced alterations in diastolic Ca(2+) level, amplitude, time-to-peak, and the decay time of both electrically and caffeine-induced Ca(2+) transients measured by spectrofluorometry in isolated ventricular myocytes of the 7-day CIH group were less than that of the normoxic group, suggesting an involvement of altered Ca(2+) handling of the sarcoplasmic reticulum (SR) and sarcolemma. We further determined the protein expression and activity of (45)Ca(2+) flux of SR-Ca(2+)-ATPase, ryanodine receptor (RyR) and sarcolemmal Na(+)/Ca(2+) exchange (NCX) in ventricular myocytes from the CIH and normoxic groups before and during I/R. There were no changes in expression levels of the Ca(2+)-handling proteins but significant increases in the RyR and NCX activities were remarkable during I/R in the CIH but not the normoxic group. The augmented RyR and NCX activities were abolished, respectively, by PKA inhibitor (0.5 microM KT5720 or 0.5 microM PKI(14-22)) and PKC inhibitor (5 microM chelerythrine chloride or 0.2 microM calphostin C) but not by Ca(2+)/calmodulin-dependent protein kinase II inhibitor KN-93 (1 microM). Thus, CIH confers cardioprotection against I/R injury in rat cardiomyocytes by altered Ca(2+) handling with augmented RyR and NCX activities via protein kinase activation.

Chronic Intermittent Hypobaric Hypoxia Ameliorates Ischemia/Reperfusion-Induced Calcium Overload in Heart via Na+/Ca2+Exchanger in Developing Rats

“…These data suggest that the anti-calcium overload effect of CIHH might be one of the mechanisms for cardioprotection of CIHH in the developing rat. It has been shown that the cardioprotective effects of CIHH in the adult rat are related to the maintenance of calcium homeostasis via activation of PKC isoforms [34]. Similarly, we found that the anti-calcium overload effect of CIHH in developing rats was inhibited by the PKC inhibitor, suggesting that the activation of PKC contributes to the Ca 2+ homeostasis in CIHH cardioprotection.…”

“…It was reported that enhanced gene expression of NCX attenuates ischemic and hypoxic contractile dysfunction [39]. A previous study of the adult heart has shown that, although CIHH has little effect on the myocardial NCX1 protein level, CIHH maintains NCX activity during I/R [26,34]. In the present study, CIHH-treated developing rats displayed an increase in NCX1 protein levels with decreased [Ca 2+ ] i in myocardium during I/R, suggesting that the increase in the NCX protein expression contributes to the anti-calcium overload effects of CIHH.…”

Apelin decreases the SR Ca2+content but enhances the amplitude of [Ca2+]itransient and contractions during twitches in isolated rat cardiac myocytes

“…C[Ca 2ϩ ]i transient amplitude was used as a measurement of SR Ca 2ϩ content (22,51,54). In the presence of caffeine, the elimination of Ca 2ϩ is mainly attributed to NCX.…”

Hypoxia. 4. Hypoxia and ion channel function

“…I/R leads to decreased forward activity of NCX, or reversal of its function, with subsequent accumulation of [Ca 2ϩ ] i , prolongation of action potentials, and risk of arrhythmias (139,229). Based on measurements of Ca 2ϩ transients in cardiomyocytes, long-term IH preconditioning had no effect on baseline (preischemic) NCX activity or protein quantity; however, IH diminished ischemia-induced prolongation of Ca 2ϩ transients either induced by electric stimulation or by Ca 2ϩ release from the SR (262). Furthermore, it has been shown recently that NCX mRNA is increased following IH exposure in mice hearts (37).…”

“…Furthermore, it has been shown recently that NCX mRNA is increased following IH exposure in mice hearts (37). NCX activity was not influenced by IH when cells were exposed to PKC inhibitors, whereas PKA and CaMK inhibitors had no effect (262). Besides these preconditioning-related effects, NCX plays crucial role in IH-induced development of left ventricular dilation and systolic dysfunction (37).…”