Cyclosporine A-enhanced cardioplegia preserves mitochondrial basal respiration after ischemic arrest

Background: Mitochondrial permeability transition pore (mPTP) opening plays a crucial role in cell death during ischemia-reperfusion injury (IRI). Cyclosporine A (CsA) inhibits mPTP opening. This study aimed to investigate the effects of CsA treatment during cardioplegia on the mitochondrial function and cardiac IRI. Methods: Landrace pigs (52.9 +/- 3.7 kg) were subjected to midline sternotomy, cardiopulmonary bypass at 34 degrees C and 90 minutes of cardiac arrest. They received either a single shot of standard 4 degrees C cold histidine-tryptophan-alpha-ketoglutarate (HTK)-Bretschneider solution (n = 11) or HTK-Bretschneider plus 1.2 mg/L CsA (histidine-tryptophan-alpha-ketoglutarate plus cyclosporine A (HTK/CsA); n = 11). During reperfusion global left-ventricular function was assessed and myocardial biopsies were harvested at baseline, during ischemia and 45 minutes following reperfusion. High-resolution respirometry and hydrogen peroxide production were measured. Immunohistochemical stainings for apoptosis-inducing factor and hypoxia-inducible factor-1 alpha as well as a flow cytometry-based JC-1 mitochondrial membrane potential assay were performed. Results: Hemodynamic parameters were comparable between both groups. The cytochrome C release (HTK: 930.3 +/- 804.4 pg/mg, HTK/CsA: 699.7 +/- 394.0 pg/mg, p = 0.457) as well as PGC1 alpha content (HTK: 66.7%, HTK/CsA: 33.3%, p = 0.284) was lower in the HTK/CsA group. Respiratory measurements revealed that the oxygen flux under basal respiration was higher in the HTK/CsA group (8.2 +/- 1.3 pmol center dot O-2 center dot s(-1)center dot mg(-1)center dot ww) than in the HTK group (3.8 +/- 1.4 pmol center dot O-2 center dot s(-1)center dot mg(-1)center dot ww, p = 0.045). There were no significant differences regarding histological surrogates of apoptosis and necrosis. Conclusions: Supplementing cardioplegic solutions with CsA enhances the basal mitochondrial respiration thereby exerting a cardioprotective effect and diminishing IRI-induced damage. CsA seems to preserve mitochondrial function via non-ROS related pathways.