In this study, experiments were designed to determine if peroxisome proliferator-activated receptor (PPAR) alpha agonists could decrease myocardial ischemia/reperfusion injury after cardioplegia-induced cardiac arrest under cardiopulmonary bypass, attenuate the appearance of cardiomyocytic apoptosis, and decrease the damage of reactive oxygen species. Cardiomyocytic apoptosis occurs after cardiopulmonary bypass surgery. Reactive oxygen species and peroxynitrite generated during ischemia/reperfusion initiate the formation of single-strand DNA breaks. Peroxisome proliferator-activated receptors (PPARs) activators had an important role in alleviating myocardial apoptosis. Four groups of New Zealand white rabbits (10 in each group, each 2.5-3.5 kg) underwent cardiopulmonary bypass. Thirty minutes before surgery, one group received WY14643 (a PPAR-alpha agonist, 1 mg kg(-1)) and another received 15D-PGJ2 (a PPAR-gamma agonist; 0.3 mg kg(-1)). The ascending aorta was cross-clamped for 60 min, whereas intermittent cold crystalloid cardioplegic solution was infused into the aortic root every 20 min. The myocardium of the reperfused hearts and control hearts were harvested and studied in vitro for evidence of apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method and Western blot analyses of cytochrome c and apoptosis-inducing factor. The reactive oxidative insults were checked using enzyme-linked immunosorbent assay to detect plasma cytokine levels. The occurrence of cardiomyocytic apoptosis and elevation of plasma cytokines were significantly lower in the group receiving PPAR-alpha agonists than in the other groups. Western blot analysis of apoptosis-inducing factor and cytochrome c revealed similar patterns. PPAR-alpha activation could diminish postischemic cardiomyocytic apoptosis and reactive oxygen species injuries after global cardiac arrest under cardiopulmonary bypass, possibly via prevention of both caspase-dependent and caspase-independent apoptotic pathways.
Nitric oxide (NO) prevents the myocardial apoptosis and dysfunction resulting from cardioplegia-induced cardiac arrest (CCA) under cardiopulmonary bypass (CPB). Inasmuch as CCA-induced myocardial dysfunction is associated with acute ischemia/reperfusion (I/R) and inflammatory response, which activates nuclear factor kappaB (NF-kappaB) translocation, we assessed the hypothesis that the detrimental effects of CCA under CPB result from NO imbalance inducing NF-kappaB activation. New Zealand white rabbits (10 in each group, each 2.5-3.5 kg) received total CPB. Rabbits were weaned from CPB and reperfused for 4 h before the hearts were harvested. Blood was sampled at various time points. Nitric oxide donor or NO synthase inhibitor was added into the cardioplegic solution. The ascending aorta was cross-clamped for 60 min, whereas cold crystalloid cardioplegic solution was intermittently infused into the aortic root every 20 min. The myocardia of the reperfused hearts and control hearts were harvested and studied for evidence of apoptosis, I/R-induced proinflammatory gene expression, and inflammatory cytokine production by cardiomyocytes. Pretreatment of the cardiomyocytes with exogenous NO prevented the I/R-induced proinflammatory effects. The inflammatory and apoptotic responses of cardiomyocytes could be lessened by restoring NO concentration via modulation of the (1) nuclear translocation of NF-kappaB, (2) inducible NO synthase mRNA expression, (3) cytochrome c production, and (4) occurrence of apoptosis. Cardioplegia-induced cardiac arrest under CPB can decrease endogenous NO production, which can be restored with exogenous NO supplementation. Exogenous NO can ameliorate the myocardial inflammatory response by inhibition of NF-kappaB translocation, inflammatory gene expression, inducible NO synthase expression, and cytochrome c production.
Cardiomyocytic apoptosis occurs after cardiopulmonary bypass (CPB) despite the use of perfusion techniques and cardioplegic solutions. Reactive oxygen species (ROS) cause single-strand DNA breaks and activate nuclear poly(ADP-ribose) polymerase (PARP), which leads to cellular damage. Therefore, the inhibition of PARP might protect cardiomyocytes from oxidative injuries. In this study, experiments were designed to determine whether a PARP inhibitor could decrease the myocardial ischemia/reperfusion injury after cardioplegia-induced global cardiac arrest under CPB, attenuate the appearance of cardiomyocytic apoptosis, and decrease damage from ROS. New Zealand white rabbits (10 in each group) were subjected to total CPB. Rabbits were weaned from CPB and reperfused for 4 h before the hearts were harvested. 3-Aminobenzamide and/or 3-aminobenzoic acid was added to the cardioplegic solution. The ascending aorta was cross-clamped for 60 min while intermittent cold crystalloid cardioplegic solution was infused into the aortic root every 20 min. The reperfused hearts were harvested and studied for evidence of apoptosis using the TUNEL method and Western blot analyses. The oxidative insults were checked using ELISA to detect plasma isoprostane and cytokines levels. The occurrence of cardiomyocytic apoptosis was significantly less in PARP inhibitor recipients than in PARP-inhibitor-naive controls. Plasma isoprostane and various cytokines were significantly elevated in PARP-inhibitor-naive controls but significantly reduced in PARP inhibitor recipients. Western blot analysis revealed similar patterns. PARP inhibitor-supplemented crystalloid cardioplegic solution diminished postischemic cardiomyocytic apoptosis and ROS-mediated injuries after global cardiac arrest under CPB, possibly via inhibiting both caspase-dependent and -independent apoptotic pathways, which also preserved postischemic myocardial contractility.
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