Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion.
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.
Yeung
Hang Mee
HM
Dept. of Physiology, University of Hong Kong, Pokfulam, Hong Kong.
Kravtsov
Gennadi M
GM
Ng
Kwong Man
KM
Wong
Tak Ming
TM
Fung
Man Lung
ML
D000818:Animals; D001835:Body Weight; D002110:Caffeine; D002118:Calcium / Q000378:metabolism*; D004594:Electrophysiology; D005786:Gene Expression Regulation; D006321:Heart / Q000033:anatomy & histology; D006352:Heart Ventricles / Q000166:cytology; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009929:Organ Size; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013997:Time Factors
D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D012964:Sodium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D010100:Oxygen; D002118:Calcium