Inhibition of Poly(adp-Ribose) Polymerase Reduces Cardiomyocytic Apoptosis After Global Cardiac Arrest Under Cardiopulmonary Bypass

Abstract

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.

Poly(ADP-ribose) polymerase activity in different pathologies – The link to inflammation and infarction

“…Also, cardiopulmonary bypass leads to induction of apopto sis in cardiac tissue. Adding 3AB to the cardioplegic solution in cardiopulmonary bypassed hearts of rabbits diminished cardiomy ocyte apoptosis and reduced the expression of pro inflammatory cytokines (Yeh et al, 2006a).…”

Strategies for Pharmacological Organoprotection during Extracorporeal Circulation Targeting Ischemia-Reperfusion Injury

“…In the following years 3-aminopenzamide was used in experimental models of stroke, renal ischemia, myocardial infarction, or heart transplantation and it was found that in all cases application of 3-aminobenzamide prior to cellular injury led to a better outcome of the examined organs (Chatterjee et al, 2000 ; Liaudet et al, 2001 ; Fiorillo et al, 2003 ; Koh et al, 2005 ). In a more recent study 3-aminobenzamide was tested in a rabbit model of CPB (Yeh et al, 2006 ). The authors could demonstrate that PARP-inhibition resulted in a significant decrease in cytokine levels and as a consequence a reduction of ROS, which in turn led to less apoptosis of cardiomyocytes and to improved contractile function of the hearts.…”

Remote Ischaemic PrEconditioning of Human Myocardium (RIPE): study protocol for a double-blinded randomised controlled trial

“…Finally, it is believed that remote preconditioning acts through its influence on mitochondria [1,2] similarly to ischaemic preconditioning. Our study will be one of very few trials examining its influence on mitochondrial structure and induction of apoptosis and certainly the first to study this phenomenon in human myocardium.…”