Sanglifehrin A Has No Protective Effects in Non‐reperfused Myocardial Infarction: the Role of Mitochondria

BackgroundExcessive reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) formation due to mitochondrial dysfunction is one of the hallmarks of heart failure. The mPTP plays a critical role in pathogenesis of myocardial infarction (MI)/ischemia‐reperfusion (IR). Cyclopilin D (CypD) activation leads to mPTP formation thereby stimulating excessive ROS production and subsequent protein oxidation. Inhibition of CypD has been linked to cardioprotection through inhibition of mPTP formation and therefore mitochondrial dysfunction. However, failure of recent CIRCUS clinical trials indicates the necessity to further study the efficacy of CypD inhibition during MI/IR injury.HypothesisInhibition of CypD by sanglifehrin A (SfA) protects the heart from reperfused but not non‐reperfused MI by preserving mitochondrial and cardiac function.MethodsMI was performed in female rats (200–250 g) by coronary artery ligation (CAL) for 30 min followed by 2‐ and 28‐ day post‐surgery with or without reperfusion. The animals were divided in the following groups: i) Sham (S, no MI); ii) Sham+SfA (SS); iii) MI (I, no reperfusion); iv) I+SfA (IS); v) MI+reperfusion (IR); and vi) IR+SfA (IRS). SfA (5 mg/kg, IV) was administered 25 min after the start of sham surgery or MI. Cardiac and left ventricular mitochondrial functions were analyzed at 2‐ and 28‐days post‐surgery.ResultsSfA significantly improved ejection fraction (EF%) after 2 (28±2 vs. 53±3) and 28 (35±3 vs. 44±2) days in reperfused hearts. 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. Left ventricular respiratory control index (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 but not after 28 days. Formation of the mPTP was the same in all groups at 2 and 28 days. An increase in ROS production was observed in permanent occluded hearts (10.0±0.8 vs 7.3±0.6) after the addition of 1 mM calcium, and SfA significantly reduced protein oxidation in reperfused hearts (16.2±1.4 vs 21.8±2.1) at 2 days. SfA significantly reduced ROS production, at 1 mM calcium, in all groups at 28 days although no differences were detected in protein oxidation levels. A 14% increase in respirasome content was observed in IR hearts at 2 days and a 13% in permanent occluded hearts at 28 days. 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.ConclusionCypD inhibition has cardioprotective effects in reperfused infarcted hearts but it has no beneficial effects in hearts with non‐reperfused MI. Hearts of female rats presumably develop compensatory mechanisms post‐MI that preserve mitochondrial function in response to oxidative stress.Support or Funding InformationSupported by the American Physiological Society Porter Physiology Development Fellowship and the National Institutes of Health (Grants SC1HL118669, SC1GM128210)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.