Reduction of myocardial reperfusion injury by an inhibitor of poly (ADP-ribose) synthetase in the pig

Bowes, Joanne; Ruetten, Hartmut; Martorana, P. A.; Stockhausen, Hannelore; Thiemermann, Christoph

doi:10.1016/s0014-2999(98)00638-4

Cited by 42 publications

(28 citation statements)

References 24 publications

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“…DNA single-strand breakage is the obligatory trigger of PARP activation (1,2,7,34), which in turn may result in rapid depletion of the intracellular NAD ϩ and ATP pools, thus slowing the rate of glycolysis and mitochondrial respiration, which eventually leads to cellular dysfunction and death. The importance of the PARP pathway is well documented in various models of myocardial ischemia-reperfusion injury (another condition in which oxidative stress plays a key pathogenetic role) (4,(35)(36)(37)(38)(39)(40)(41)(42). Based on the results of the current study, we conclude that the "reactive oxygen/ nitrogen species-DNA injury-PARP activation" pathway also plays a pathogenetic role in the development of diabetic cardiomyopathy.…”

Section: Discussionsupporting

confidence: 60%

The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes

et al. 2002

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Patients with diabetes exhibit a high incidence of diabetic cardiomyopathy and vascular complications, which underlie the development of retinopathy, nephropathy, and neuropathy and increase the risk of hypertension, stroke, and myocardial infarction. There is emerging evidence that the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) importantly contributes to the development of endothelial dysfunction in a streptozotocin-induced model of diabetes. We investigated the role of PARP activation in the pathogenesis of cardiac dysfunction in streptozotocin-induced and genetic (nonobese diabetic) models of diabetes in rats and mice. Development of diabetes was accompanied by hyperglycemia, cardiac PARP activation, a selective loss of endothelium-dependent vasodilation in the thoracic aorta, and an early diastolic dysfunction of the heart. Treatment with a novel potent phenanthridinonebased PARP inhibitor, PJ34, starting 1 week after the onset of diabetes, restored normal vascular responsiveness and significantly improved cardiac dysfunction, despite the persistence of severe hyperglycemia. The beneficial effect of PARP inhibition persisted even after several weeks of discontinuation of the treatment. Thus, PARP activation plays a central role in the pathogenesis of diabetic cardiovascular (cardiac as well as endothelial) dysfunction. PARP inhibitors may exert beneficial effects against the development of cardiovascular complications in diabetes. Diabetes 51:514 -521, 2002 P oly(ADP ribose) polymerase (PARP), also known as poly(ADP ribose) synthetase (PARS), is an abundant nuclear enzyme of eukaryotic cells that participates in DNA repair in response to genotoxic stress. When activated by DNA single-strand breaks, PARP initiates an energy-consuming cycle by transferring ADP ribose units from NAD ϩ to nuclear proteins. This process results in rapid depletion of the intracellular NAD ϩ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death (1-7). Overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidant stress, including myocardial reperfusion injury (4), stroke (3), shock (7,8), and autoimmune ␤-cell destruction (5,6). Recently, we reported that the activation of PARP importantly contributes to the development of endothelial dysfunction in a streptozotocin (STZ)-induced model of diabetes in mice (9,10).Cardiovascular complications are the most common cause of morbidity and mortality in diabetic patients. The presence of myocardial dysfunction independent of coronary artery disease in diabetes, known as "diabetic cardiomyopathy," has been well documented in both humans and animals (11-15). Diabetic cardiomyopathy is characterized by an early diastolic dysfunction and a late systolic one, with intracellular retention of calcium and sodium and loss of potassium. The mechanism of diastolic dysfunction remains unknown, but it does not appear to be due to cha...

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Section: Discussionsupporting

confidence: 60%

The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes

et al. 2002

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“…Although we have not directly monitored NAD ϩ and ATP levels, such depletions occur in other models in which PARP inhibition protects from tissue damage. The protective paradigm of PARP inhibition after DNA damage has been demonstrated for numerous other models of cell death, including cerebral ischemia (10)(11)(12)(13)26), myocardial ischemia (27)(28)(29)(30), N-methyl-D-aspartic acid receptor-mediated excitotoxicity in the lung (31), methamphetamine neurotoxicity (32,33), and MPTP toxicity (34)(35)(36). In all of these cases, a lack of PARP activity, through either genetic disruption or pharmacologic inhibition, provides impressive protection from cell death after DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Pieper

Brat

Krug

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

277

180

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Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD ؉ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP ؊͞؊), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP ؉͞؊ animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.Type I diabetes (insulin-dependent diabetes mellitus) is a chronic metabolic disorder characterized by a loss of pancreatic islet B cell mass, decreased serum insulin, and hyperglycemia. Although the pathogenic mechanisms of this disease have not been fully characterized, genetic, environmental, and autoimmune factors have been postulated. In particular, development of this disorder is postulated to proceed through generation of oxygen radicals during prediabetic pancreatic islet inflammation (1, 2). One possible mechanism is that autoimmune activation of macrophages damages B cells through release of massive amounts of NO after inducible NO synthase activation, as damage elicited when islets are cocultured with macrophages is prevented by inhibition of NO synthase (3).Focal cerebral ischemic damage is also associated with NO release leading to DNA damage elicited by reactive oxygen species, including peroxynitrite formed from NO. Downstream of this DNA damage, the enzyme poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is stimulated. Nuclear PARP is activated by DNA fragments to transfer branched chains of up to 200 ADP ribose groups from NAD ϩ to acceptor proteins in the nucleus, including histones and PARP itself. PARP activation plays a role in DNA repair, particularly the base excision repair process (4-8), in response to moderate amounts of DNA damage. With excessive DNA damage, however, PARP is so highly activated that its substrate NAD ϩ is critically depleted (9). NAD ϩ is an important enzyme in energy metabolism, and its depletion results in lower ATP production. As ATP is also consumed in efforts to resynthesize NAD ϩ , cells can die from energy loss. Cerebral ischemic damage is greatly diminished in mice with targeted deletion of PARP (PARP Ϫ͞Ϫ) (10, 11) and in animals treated with PARP inhibitors (12, 13). A role of PARP activation in pancreatic damage is also suggested by protection through PARP inhibition of pancreatic islet cells from NO-mediated killing (14, 15). Furthermore, in vitro pancreatic islet cells from PARP Ϫ͞Ϫ mice are resistant to NAD ϩ depletion after exposure to either NO or other reactive oxygen intermediates generated th...

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“…If PARP activation exceeds a certain limit, it can lead to cellular NAD ϩ and ATP depletion, ultimately resulting in cell death (Habon et al, 2001;Halmosi et al, 2001;Virag and Szabo, 2002;Szabo et al, 2004). We and other investigators have already shown that PARP inhibitors can efficiently reduce oxidative myocardial damage during ischemia-reperfusion both in isolated heart perfusion and in in vivo myocardial infarction models (Zingarelli et al, 1997;Bowes et al, 1998;Docherty et al, 1999;Halmosi et al, 2001). Recent studies, however, have challenged the original dogma that protection by PARP inhibitors relies exclusively on the preservation of NAD ϩ and ATP stores and suggested that PARP inhibitors may modify the activation state of signaling routes and gene expression (Kovacs et al, 2004;Szabo et al, 2004;Veres et al, 2004;Zingarelli et al, 2004).…”

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confidence: 99%

The Role of Akt and Mitogen-Activated Protein Kinase Systems in the Protective Effect of Poly(ADP-Ribose) Polymerase Inhibition in Langendorff Perfused and in Isoproterenol-Damaged Rat Hearts

Pálfi

Tóth²,

Kulcsár

et al. 2005

J Pharmacol Exp Ther

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Blocking poly(ADP-ribosyl)ation of nuclear proteins protects the heart from ischemia-reperfusion injury. In addition, activation of Akt and mitogen-activated protein kinase (MAPK) cascades also plays a pivotal role in the survival of cardiomyocytes during ischemia-reperfusion; however, the potential interplay between these pathways is yet to be elucidated. We therefore tested the hypothesis whether poly(ADP-ribose) polymerase (PARP) inhibition can modulate Akt and MAPK signaling of ischemic-reperfused rat hearts. A novel PARP inhibitor, L-2286 [2-[(2-piperidin-1-yletil)thio]quinazolin-4(3H)-one] was administered during ischemia-reperfusion in Langendorff perfused rat hearts and in isoproterenol-induced myocardial infarction. Thereafter, the cardiac energy metabolism, oxidative damage, and the phosphorylation state of Akt and MAPK cascades were monitored. L-2286 exerted significant protective effect against ischemia-reperfusion-induced myocardial injury in both experimental models. More importantly, L-2286 facilitated the ischemia-reperfusion-induced activation of Akt, extracellular signalregulated kinase, and p38-MAPK in both isolated hearts and in vivo cardiac injury. By contrast, isoproterenol-induced rapid c-Jun N-termainal kinase activation was repressed by L-2286. Here, we provide evidence for the first time that PARP inhibition beneficially modulates the cardiac Akt and MAPK signaling in ex vivo and in vivo ischemia-reperfusion models. We therefore propose that this novel mechanism may contribute to the cardioprotective properties of PARP inhibitors.Enhanced activation of poly(ADP-ribose) polymerase (PARP) enzyme is a major contributor to oxidative stressinduced cell dysfunction and tissue injury (Virag and Szabo, 2002;Szabo et al., 2004). Reactive oxygen species and peroxynitrite formation expedites the ischemia-reperfusion-induced cardiac injury and causes lipid peroxidation, protein oxidation, and single-strand DNA brakes (Habon et al., 2001;Halmosi et al., 2001). Single-strand DNA brakes can activate the nuclear PARP, which ADP-ribosylates different nuclear proteins at the expense of cleaving NAD ϩ . If PARP activation exceeds a certain limit, it can lead to cellular NAD ϩ and ATP depletion, ultimately resulting in cell death (Habon et al., 2001;Halmosi et al., 2001;Virag and Szabo, 2002;Szabo et al., 2004). We and other investigators have already shown that PARP inhibitors can efficiently reduce oxidative myocardial damage during ischemia-reperfusion both in isolated heart perfusion and in in vivo myocardial infarction models (Zingarelli et al

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Reduction of myocardial reperfusion injury by an inhibitor of poly (ADP-ribose) synthetase in the pig

Cited by 42 publications

References 24 publications

The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes

The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

The Role of Akt and Mitogen-Activated Protein Kinase Systems in the Protective Effect of Poly(ADP-Ribose) Polymerase Inhibition in Langendorff Perfused and in Isoproterenol-Damaged Rat Hearts

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