Untitled

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA injury in eukaryotic cells and has been implicated in cell dysfunction in reperfusion injury. In this study we investigated the role of PARP-1 on apoptosis in early myocardial reperfusion injury. Mice genetically deficient of PARP-1 (PARP-1-/-) and wild-type littermates were subjected to myocardial ischemia and reperfusion. Myocardial injury was assessed by measuring the serum levels of creatine phosphokinase and oligonucleosomal DNA fragments in the infarcted area. Expression of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax, was analyzed by Western blot. Activation of caspases, important executioners of apoptosis, and activation of the nuclear factor kappa B (NF-kappa B) pathway were evaluated. Gene expression profiles for apoptotic regulators between PARP-1-/- and wild-type mice also were compared. Myocardial damage in PARP-1-/- mice was reduced significantly, as indicated by lower serum creatine phosphokinase levels and reduction of apoptosis, as compared with wild-type mice. Western blot analyses showed increased expression of Bcl-2, which was associated with reduction of caspase-1 and caspase-3 activation. This cardioprotection was associated with significant reduction of the activation of I kappa B kinase complex and NF-kappa B DNA binding. Microarray analysis demonstrated that the expression of 29 known genes of apoptotic regulators was significantly altered in PARP-1-/- mice compared with wild-type mice, whereas 6 known genes were similarly expressed in both genotypes. The data indicate that during reperfusion absence of PARP-1 leads to reduction of myocardial apoptosis, which is associated with reduced NF-kappa B activation and altered gene expression profiles.

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

“…3-AB significantly improved the outcome of myocardial dysfunction, as evidenced by a reduction in creatine phosphokinase levels, diminished infarct size, and preserved the ATP pools (Zingarelli et al, 1997). These findings were subsequently confirmed and extended into various other models using PARP inhibitors of increasing selectivity and potency (Thiemermann et al, 1997; Bowes et al, 1998a; Bowes et al, 1998b; Docherty et al, 1999; Liaudet et al, 2001a, Liaudet et al, 2001b, Faro et al, 2002; Zingarelli et al, 2003; Khan et al, 2003; Kaplan et al, 2005; Song et al, 2008; Eltze et al, 2008; Roesner et al, 2010; Zhang et al, 2012). Furthermore, Zingarelli also demonstrated that PARP deficient mice are protected against myocardial reperfusion injury (Zingarelli et al, 1998; Yang et al, 2000).…”

Inhibition of the activity of poly (ADP‐ribose) polymerase reduces heart ischaemia/reperfusion injury via suppressing JNK‐mediated AIF translocation

“…In heart I/R injury the hyper-activation of PARP is able to disturb the energy generation process and the mitochondrial function. PARP can also regulate the expression of various proteins and cytokines such as ICAM-1 [ 28 ], AP-1 complex [ 29 ], nf-kb [ 30 ], TNF-α and IL-10 [ 31 ]. PARP inhibition or PARP deficiency have been shown to suppress the cytokines expression in vitro or in vivo .…”

Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles

“…Ppif −/− mice, which lack the crucial component for MPT­driven regulated necrosis CypD, are protected against cardiac ischaemia–reperfusion injury 259,260 , angiotensin­II­induced cardiomyopathy 261 , and arrhythmia (in this last case, perhaps also linked to preserved Ca 2+ fluxes) 262 . The deletion of Parp1 , which encodes poly(ADP­ribose) polymerase 1 (a nuclear DNA repair enzyme that is required for parthanatos), mediates beneficial effects in mouse models of ischaemia–reperfusion injury 263,264 and atherogenesis 265 . Moreover, both Ripk3 −/− mice (which lack a critical regulator of necroptosis) and mice engineered to overexpress dominant­negative CaMKII in the heart are protected against ischaemia–reperfusion injury and the cardiotoxic effects of doxorubicin 266 .…”