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

Abstract

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

Nuclear ADP-Ribosylation Reactions in Mammalian Cells: Where Are We Today and Where Are We Going?

“…The first indication is from inhibitor studies, which demonstrated that several different nonspecific PARP inhibitors could enhance the endotoxin-induced or ischemia-reperfusion-induced activation of phosphatidylinositol 3-kinase (PI-3-kinase)/AKT/PKB, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase in ex vivo models. The rapid activation of the JNK-1 cascade was blocked in the presence of nonspecific PARP inhibitors (310,423,424). As mentioned above, a recent report provided indirect evidence that activation of JNK-1 is required for PARP-1-dependent mitochondrial dysfunction, AIF translocation, and subsequent cell death (443).…”

“…Several recent studies indicate that PARP-1-catalyzed poly-ADP-ribosylations may affect signaling pathways through negative or positive modulation of distinct kinase activities, which play a significant role in cell survival and cell death (310,399,423,424). The first indication is from inhibitor studies, which demonstrated that several different nonspecific PARP inhibitors could enhance the endotoxin-induced or ischemia-reperfusion-induced activation of phosphatidylinositol 3-kinase (PI-3-kinase)/AKT/PKB, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase in ex vivo models.…”

PARP-1-induced cell death through inhibition of the MEK/ERK pathway in MNNG-treated HeLa cells

“…Recent studies using PARP inhibitors suggest that poly(ADP-ribosyl)ation may affect signaling pathways which are linked to cell survival [25,26]. To better understand the implication of PARP-1 activation in cell death, we analyzed the effect of PAR synthesis on the MEK/ERK signaling pathway in HeLa cells exposed to the alkylating agent N-methyl-N 0 -methyl-nitro-N-nitrosoguanidine (MNNG).…”

Pivotal Role of Akt Activation in Mitochondrial Protection and Cell Survival by Poly(ADP-ribose)polymerase-1 Inhibition in Oxidative Stress

“…PARP inhibitors show pronounced protection against myocardial ischemia (16), neuronal ischemia (17,18), acute lung inflammation (19), acute septic shock (20), zymogen-induced multiple organ failure (21), and diabetic pancreatic damage (22)(23)(24), providing evidence for the role of excessive PARP-1 activation in cell death. It is believed that by preventing excessive NAD ϩ and ATP utilization, PARP inhibitors protect cells against oxidative damage, but some recent data suggest a more complex mechanism for the cytoprotection (25,26). There is evidence that PARP activation can contribute to exaggeration of mitochondrial damage (27) and mitochondrial reactive oxygen species production (28), indicating that PARP activation can modulate processes outside of the nucleus.…”