Cardiomyocytic Apoptosis Following Global Cardiac Ischemia and Reperfusion Can Be Attenuated by Peroxisome Proliferator-Activated Receptor Α but Not Γ 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.

Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction

“…It was observed during analysis that 2-5% myocytes at the most demonstrated TUNEL positive nuclei by 7 days post-sepsis. These data are consistent with an in vivo study, in which 8% apoptotic nuclei were reported in a global cardiac ischemia reperfusion injury model in the rabbit (Yeh et al, 2006). An increased immunofluorescence of caspase-3 distributed throughout the cell cytosol was observed in the septic LV sections.…”

Role of fenofibrate alone and in combination with telmisartan on renal ischemia/reperfusion injury

“…31,32 Fenofibrate, PPAR-a agonist, was proved effective in reducing the generation of ROS, overexpression of TNF-a, and excess NO production observed with oxidative and inflammatory tissue injuries. 10,17,33 The antioxidant and anti-inflammatory effects of fenofibrate are related to its ability to suppress the protein expression for NADPH oxidase, TNF-a, and inducible nitric oxide synthase by inhibiting the phosphorylation of p38 MAPK (mitogen-activated protein kinase). Fenofibrate, therefore, prevents the activation of the nuclear factor-kB signaling pathway, which promotes the transcription of NADPH oxidase, TNF-a, and inducible nitric oxide synthase genes.…”

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

“…This in turn elevates EET levels, which mediate blood vessel dilation and lowers blood pressure (BP), especially in the setting of hypertension (2,3). Diverse sEH inhibitors limit injury in a variety of diseases (4), providing broad cardiovascular protection (5) against hypertension (6,7), ischemia and reperfusion injury (8,9), hypertrophy, and heart failure (10), as well as inflammation (11,12). Consistent with the therapeutic potential of hydrolase inhibitors, sEH null mice are protected from pathological interventions (13).…”