Attenuation of mitochondrial, but not cytosolic, Ca2+ overload reduces myocardial injury induced by ischemia and reperfusion.
OBJECTIVE
Attenuation of mitochondrial Ca2+ ([Ca2+]m), but not cytosolic Ca2+ ([Ca2+]c), overload improves contractile recovery. We hypothesized that attenuation of [Ca2+]m, but not [Ca2+]c, overload confers cardioprotection against ischemia/reperfusion-induced injury.


METHODS
Infarct size from isolated perfused rat heart, cell viability, and electrically-induced Ca2+ transient in isolated rat ventricular myocytes were measured. We determined the effects of BAPTA-AM, a Ca2+ chelator, at concentrations that abolish the overload of both [Ca2+]c and [Ca2+]m, and ruthenium red, an inhibitor of mitochondrial uniporter of Ca2+ transport, at concentrations that abolish the overload of [Ca2+]m, but not [Ca2+]c, on cardiac injury induced by ischemia/reperfusion.


RESULTS
Attenuation of both [Ca2+]m and [Ca2+]c by BAPTA-AM, and attenuation of [Ca2+]m, but not [Ca2+]c, overload by ruthenium red, reduced the cardiac injury observations, indicating the importance of [Ca2+]m in cardioprotection and contractile recovery in response to ischemia/reperfusion.


CONCLUSIONS
The study has provided unequivocal evidence using a cause-effect approach that attenuation of [Ca2+]m, but not [Ca2+]c, overload is responsible for cardioprotection against ischemia/reperfusion-induced injury. We also confirmed the previous observation that attenuation of [Ca2+]m, but not [Ca2+]c, by ruthenium red improves contractile recovery following ischemia/reperfusion.
Cao
Chun-mei
CM
The Institute of Molecular Medicine, Peking University, Beijing 100871, China.
Yan
Wing-yee
WY
Liu
Jing
J
Kam
Kenneth W L
KW
Zhan
Shi-zhong
SZ
Sham
James S K
JS
Wong
Tak-ming
TM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology
D002614:Chelating Agents; D012430:Ruthenium Red; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D002118:Calcium