Ischemia–reperfusion induces myocardial infarction through mitochondrial Ca2+ overload

Abstract

Both mitochondria and the sarcoplasmic reticulum (SR) are essential for myocardial homeostasis and control of cardiac function. Uptake of Ca2+ from the cytosol into SR is mediated by the Ca2+-dependent ATPase SERCA2a, which is reversibly inhibited by phospholamban (PLN). We previously showed that removal of PLN inhibition of SERCA2a with an antibody to (anti-) PLN reduces cytosolic Ca2+ overload, thereby attenuating the spread of contraction bands and fodrin proteolysis, during reperfusion after cardiac ischemia. We have now examined the effects of anti-PLN injection into the heart on the development of myocardial infarction (MI) after ischemia–reperfusion in rats. Whereas anti-PLN injection attenuated cytosolic Ca2+ overload, it did not affect MI size 6h after the onset of reperfusion and actually increased it at 30min. The antibody also increased the release of apoptosis-inducing factor (AIF) from mitochondria into the cytosol, indicative of enhanced opening of the mitochondrial permeability transition pore (mPTP). Administration of an mPTP blocker at the time of reperfusion or of a blocker of the mitochondrial Ca2+ uniporter significantly suppressed the release of AIF and the development of MI. These results indicate that the enhancement of SR Ca2+ loading by anti-PLN injection facilitated Ca2+ uniporter‐dependent mitochondrial Ca2+ uptake and thereby induced mPTP opening and MI development during early reperfusion. The enhancement of SR Ca2+ loading thus aggravates MI in a manner independent of cytosolic Ca2+ overload. Given that cytosolic Ca2+ overload induces contraction bands, our findings are inconsistent with a causal relation between contraction bands and MI.