Suppression of poly (ADP‐ribose) polymerase activation by 3‐aminobenzamide in a rat model of myocardial infarction: long‐term morphological and functional consequences

Abstract

1 Recent studies demonstrated that inhibition or genetic inactivation of the enzyme poly (ADPribose) polymerase (PARP) is bene®cial in myocardial reperfusion injury. PARP activation in the reperfused myocardium has been assumed, but not directly demonstrated. Furthermore, the issue whether pharmacological PARP inhibition a ords long-term functional bene®t in the reperfused myocardium has not been explored. These questions were addressed in the present study.2 In a rat model of myocardial ischemia (1 h) and reperfusion (up to 24 h), there was a marked and signi®cant activation of PARP in the ischemic borderzone, as determined by poly(ADP-ribose) (PAR) immunohistochemistry. PAR localized to the nuclei of myocytes and in®ltrating mononuclear cells. In the core of the infarction, necrotic tissues and di use PAR staining were observed. PARP activation remained markedly detectable 24 h after reperfusion. The PARP inhibitor 3-aminobenzamide (20 mg kg 71 intraperitoneally 10 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced the activation of the enzyme in myocytes. 3 3-aminobenzamide signi®cantly protected against myocardial morphological and functional alterations at 24 h post-reperfusion. Notably, infarct size was reduced, circulating creatine kinase activity was attenuated, and myocardial contractility (dP dt 71 ) was restored by 3-aminobenzamide. 4 Our results demonstrate a signi®cant and prolonged activation of PARP in the reperfused myocardium, localizing to the necrotic area and the ischaemic borderzone. Furthermore, the studies demonstrate that PARP inhibition a ords long-term bene®cial morphological and functional e ects in the reperfused myocardium. These data strengthen the notion that pharmacological PARP inhibition is a viable novel experimental approach for protection against myocardial reperfusion injury.

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…Nevertheless, the down-regulation of c-Jun is consistent with the results from many studies using PARP inhibitors or PARP silencing (Song et al, 2008;Huang et al, 2009;Mester et al, 2009;Kim et al, 2012;Radnai et al, 2012). Moreover, inhibition of neutrophil infiltration is consistent with previous findings showing similar effect of PARP inhibitors of other structural classes, as well as PARP1 deficiency in various models of ischaemia-reperfusion and inflammation Szabó, 1998;Zingarelli et al, 1998;Liaudet et al, 2001Liaudet et al, , 2002Mabley et al, 2001).…”

“…This process leads to the depletion of intracellular nicotinamide adenine dinucleotide (NAD + ) and ATP pools leading to cellular mitochondrial dysfunction and cell death, via the necrotic route (Gilad et al, 1997;Zingarelli et al, 1997;Zingarelli et al, 1998). Follow-on studies extended these findings, both using pharmacological PARP inhibitors of various classes (Thiemermann et al, 1997;Bowes et al, 1998;Docherty et al, 1999;Liaudet et al, 2001;Zingarelli et al, 2003;Zingarelli et al, 2004;Kaplan et al, 2005;Eltze et al, 2008;Oh et al, 2009;Roesner et al, 2010;Gerö et al, 2014), as well as genetically modified mice deficient in PARP1 (Zingarelli et al, 1998;Grupp et al, 1999;Pieper et al, 2000;Yang et al, 2000). The cardiac protective effect of PARP inhibitors was subsequently extended into various models of heart transplantation.…”

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP): A Comparison with Standard PARP Inhibitors

“…Available data from the literature, however, indicate no clear superiority of PARP inhibitors with good water-solubility (e.g., 3-AB, 5-AIQ, PJ34, INO-1001) over poorly water-soluble inhibitors (e.g., ISQ, GPI-6150), at least regarding reduction of infarct size in the rat heart. In line with our observation, the maximally obtainable reduction of myocardial infarct size in the rat reported in the literature was 17 to 36% (Zingarelli et al, 1997;Pieper et al, 2000;Liaudet et al, 2001;Wayman et al, 2001;Faro et al, 2002). However, the cardiac infarct size in parp-1(Ϫ/Ϫ) mice subjected to global myocardial ischemia and reperfusion is maximally decreased by 35% relative to untreated wild-type mice, possibly because of a residual poly-(ADP-ribosyl)ation activity mediated by alternative isoform(s) of PARP in this tissue (Pieper et al, 2000).…”

“…Distinct binding modes necessary for discrimination between ligands and each isoenzyme have been discovered, enabling synthesis of PARP-1 selective quinazolinones and PARP-2 selective quinoxalines (Iwashita et al, 2004a,b;Ishida et al, 2006). PARP-1 activation contributes to the tissue injury caused by ischemia and reperfusion in various organs, including heart (Eliasson et al, 1997;Thiemermann et al, 1997;Liaudet et al, 2001). A reduction in infarct size and/or improved cardiac contractility after myocardial ischemia in rats has been demonstrated for PARP inhibitors of different chemical structure [e.g., 3-AB, NA, 4-HQN, ISQ, 5-AIQ, GPI-6150, PJ34, and INO-1001 (Thiemermann et al, 1997;Zingarelli et al, 1997;Bowes et al, 1998;Docherty et al, 1999;McDonald et al, 2000;Pieper et al, 2000;Wayman et al, 2001;Faro et al, 2002)].…”

Activation of Poly(ADP-Ribose) Polymerase by Myocardial Ischemia and Coronary Reperfusion in Human Circulating Leukocytes

“…In oxidant-challenged myocytes, PARP also regulates the mitochondrialto-nuclear translocation of cell death factors such as apoptosis-inducing factor (AIF) and cytochrome c (13). In vitro experimental animal studies using perfused heart systems demonstrated that PARP inhibitors improve myocardial contractility and preserve myocardial ATP and NAD + pools during reperfusion (14)(15)(16). PARP inhibitors significantly diminish infarct size and reduce creatine phosphokinase levels and mortality in mouse, rat, pig, and rabbit models (10).…”