LAUSR

Background Opening of mitochondrial permeability transition pores (mPTP) plays a critical role in pathogenesis of myocardial infarction (MI)/ischemia-reperfusion (IR). Inhibition of cyclophilin D (CypD), a major regulator of the mPTP, is mostly used for prevention of MI/IR injury. CypD also plays an important physiological role, and controls cell metabolism through regulation of glucose uptake, FAO, and mitochondrial bioenergetics. Physiological role of CypD as well as failure of recent CIRCUS clinical trials indicate the necessity for further studies elucidating the efficacy of CypD inhibition during MI/IR injury. Hypothesis Inhibition of CypD by sanglifehrin A (SfA) has divergent effects in non-reperfused MI and reperfused MI. Methods MI was induced in adult female rats (200-250 g) by ligation coronary artery (CAL) for 30 min followed by 2- and 28-day post-surgery with or without reperfusion. The animals were studied in the following groups: i) Sham (S, no MI); ii) SS (Sham+SfA); iii) MI (no reperfusion); iv) MI+SfA; v) MI+R (MI+reperfusion); and vi) MI+RS (MI+reperfusion+SfA). SfA (5 mg/kg, IV) was administered at 25 min after a start of sham surgery or MI. Cardiac and mitochondrial functions were analyzed at 2- and 28-days post-surgery. Results SfA significantly improved cardiac function (ejection fraction, EF%) (28±2 vs. 53±3) after 2 days and at 28 days (35±3 vs. 44±2). SfA administration to permanent occluded hearts has no effect on EF% at 2 (36±4 vs. 40±4) and 28 (32±3 vs. 40±4) days. SfA has no effect on cardiac EF% at 2 and 28 days in the S group. Menstrual cycle affected post-ischemic recovery, where cycles with high estrogen levels positively correlated (r2=0.48) with an increase in EF% in reperfused MI hearts. Left ventricular RCI was significantly reduced (7.5±0.5 vs. 5.6±0.3) in animals subjected to IR when compared to controls after 2 days, however, state 3 mitochondrial respiration was unaffected. State 3 respiration and RCI was unaffected at 28 days in all groups. Mitochondrial ROS production was the same in all groups at 2 and 28 days. Conclusion Inhibition of mPTP through CypD has cardioprotective effects against reperfused MI, but not non-reperfused MI hearts after short and long post-surgery in female rats.