title: Cardiomyocytic apoptosis following global cardiac ischemia and reperfusion can be attenuated by peroxisome proliferator-activated receptor alpha but not gamma activators.
abstract: 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.
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Keelung 204, Taiwan. yehccl@cgmh.org.tw
authors.forename: Chi-Hsiao
authors.initials: CH
authors.lastname: Yeh
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Chen
authors.forename: Chieh-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Wu
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Pyng Jing
authors.initials: PJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002315:Cardiopulmonary Bypass; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000235:genetics; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006324:Heart Arrest, Induced; D020287:In Situ Nick-End Labeling; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D019210:Troponin I / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000097:blood
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D015815:Cell Adhesion Molecules; D016207:Cytokines; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D047493:PPAR alpha; D047495:PPAR gamma; D020025:Peroxisome Proliferators; D016755:Proto-Oncogene Proteins c-jun; D011743:Pyrimidines; D019210:Troponin I; D048069:Tumor Necrosis Factors; C006253:pirinixic acid; D009195:Peroxidase; D053148:Caspase 3; D020169:Caspases; D015230:Prostaglandin D2