No 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

Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme has been implicated in the pathogenesis of acute and chronic myocardial dysfunction. We have demonstrated the protective effect of PARP inhibitors against postinfarction myocardial remodeling and heart failure. The primary aim of our recent work was to compare the effect and efficacy of a potent PARP-inhibitor (L-2286) to enalapril, a widely used angiotensin-converting enzyme (ACE) inhibitor. in experimental heart failure model. Both L-2286 and enalapril were tested in a rat model of chronic heart failure after isoproterenol-induced myocardial infarction. After a 12-week treatment period, echocardiography was performed, cardiac hypertrophy and interstitial collagen deposition were assessed, and the phosphorylation state of Akt-1/GSK-3beta pathway as well as the PKC and MAPK kinases were determined. Both PARP and ACE inhibition reduced the progression of postinfarction heart failure by attenuating cardiac hypertrophy and interstitial fibrosis. More importantly, PARP inhibition increased the activity of the prosurvival signal transduction factors (Akt-1/GSK-3beta pathway, PKCepsilon). Due to these effects, L-2286 improved the systolic left ventricular function. Enalapril treatment exerted a similar, but weaker protective effect against postinfarction myocardial remodeling and heart failure. In conclusion, we demonstrated in an experimental heart failure model that L-2286 decreased the postinfarction myocardial remodeling more effectively than enalapril treatment.

Despite global abnormalities of the immune system, such as in AIDS, the incidence of only a few kinds of tumor increases, and even in the development of these tumors the degree of immunosuppression seems not to be a critical factor. This means that the known immune system has no significant role in the tumor preventing mechanism. Thus, the fact that tumors do not develop in the majority of the population during their lifetime, indicates the existence of an additional defense mechanism of the immune system. We demonstrated previously that this defense is produced by the synergistic action of certain substances of the circulatory system. Here we report that the substances taking part in the defense induced, but only when they were used together, the apoptosis of tumor cells, but not normal cells, as was detected by different methods. Other substances of the circulatory system did not show similar effects. These results further support the existence of the mentioned defense mechanism called by us the Passive Antitumor Defense System.

. 60, 1432 (1982). The reactions of l-oxyl-2,2,5,5-tetrarnethyl-3-pyrroline-3-carboxaldehyde (1). I-oxyl-2,2,5,5-tetrarnethyl-3-cyano-3-pyrroline (21, ethyl I-oxyl-2,2,S,S-tetrarnethyl-3-pyrroline-3-carbonyl carbonate (3), and N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3 carbony1)irnidazolide (4) are investigated with several nucleophiles (dialkylcadrniurn, diethyl sodio-rnalonate, magnesium enolate of ethyl hydrogen rnalonate, nitrornethane-anion) to obtain a$-unsaturated ketones, P-ketoesters, or conjugated reaction products. Aldehyde 1 is reacted with several methyl ketones (acetylrnethylene-triphenylphosphorane, acetophenone, 2-acetylpyridine, 4-phenyl-3-butyn-2-one) to give spin labeled polyenones. The reaction of 4-(1-oxyl-2,2,5,5-tetrarnethyl-3-pyrroline-3-yl)-2-butenone (24a) with ethylenediarnine gives 7,14-bis-(1-oxyl-2,2,5,5-tetrarnethyl-3-pyrroline-3-yl)-S,12-dirnethyl-1,4,8