Attenuation of mitochondrial, but not cytosolic, Ca²⁺ overload reduces myocardial injury induced by ischemia and reperfusion

Aim: 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.
Conclusion: 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.