Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the cardioprotection afforded by the late phase of ischemic preconditioning (PC) in ischemia/reperfusion (I/R) injury has been well studied, it is unknown whether this beneficial effect can be attributed to inhibition of apoptosis. We hypothesized that ischemic PC affords protection by suppressing apoptosis and examined the underlying mechanisms. Myocardial infarction was produced in mice (30-min coronary occlusion). In animals preconditioned 24 h earlier with six 4-min coronary occlusion/4-min reperfusion (O/R) cycles, there was a marked decrease in apoptosis as assessed by three different parameters: hairpin-1 assay, caspase-3 activity, and immunohistochemical analysis of active caspase-3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1). This protective effect was accompanied by increased expression of multiple antiapoptotic proteins that regulate both the mitochondria-mediated (Bcl-x(L) and Mcl-1) and the death-receptor-mediated (c-FLIP(L) and c-FLIP(S)) pathway of apoptosis and by decreased expression of the proapoptotic protein Bad. This is the first demonstration that the late phase of ischemic PC attenuates cardiac apoptosis after ischemia/reperfusion injury and that this salubrious effect is associated with a complex genetic prosurvival program that results in modulation of several key proteins involved in both the mitochondrial and the death receptor pathways of apoptosis.
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PMID:The late phase of ischemic preconditioning induces a prosurvival genetic program that results in marked attenuation of apoptosis. 1749 Jun 77

Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and four additional, recently identified poly(ADP-ribosylating) enzymes. PARP-1 is one of the most abundant nuclear proteins and functions as a DNA nick sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. On one hand, PARP is viewed as a guardian angel of genomic integrity, and inhibition of PARP has been used to facilitate the death of tumor cells alone, or in combination with antitumor agents. On the other hand, overactivation of PARP in response to oxidant- and free radical-mediated excessive DNA single strand breaks promotes cell dysfunction and necrotic type cell death in a variety of pathophysiological conditions. Pharmacological inhibition of PARP, consequently, exerts cytoprotective effects in a variety of diseases including stroke, myocardial infarction, heart failure and diabetes mellitus. The research into the role of PARP in diabetic cardiovascular injury is now supported by novel tools such as new classes of potent inhibitors of PARP as well as genetically engineered animals lacking the gene for PARP. In addition, potent PARP inhibitors have entered the stage of clinical testing. The current review provides an update on the most recent developments in the area of PARP.
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PMID:Poly(ADP-ribose) polymerase as a drug target for cardiovascular disease and cancer: an update. 1752 94

Recent studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of myocardial infarction. To explore whether NSAIDs may induce endothelial apoptosis and thereby enhance atherothrombosis, we treated human umbilical vein endothelial cells (HUVECs) with sulindac sulfide (SUL), indomethacin (IND), aspirin (ASA), or sodium salicylate (NaS), and we analyzed apoptosis. SUL and/or IND significantly increased annexin V-positive cells, cleaved poly(ADP-ribose) polymerase (PARP) and caspase-3. ASA and NaS at 1 mM did not induce PARP cleavage or caspase-3 and at 5 mM, ASA but not NaS increased apoptosis. Because peroxisome proliferator-activated receptor delta-mediated 14-3-3epsilon up-regulation was reported to play a crucial role in protecting against apoptosis, we determined whether NSAIDs suppress this transcriptional pathway. SUL, IND, and ASA (5 mM) suppressed PPARdelta and 14-3-3 proteins in a manner parallel to PARP cleavage. Neither ASA nor NaS at 1 mM interfered with PPARdelta or 14-3-3epsilon expression. SUL inhibited PPARdelta promoter activity, which correlated with 14-3-3epsilon promoter suppression. Suppression of 14-3-3epsilon was associated with increased Bad translocation to mitochondria. Neither carbaprostacylin nor 4-(3-(2-propyl-3-hydroxy-4-acetyl)-phenoxy)propyloxyphenoxy acetic acid (L-165041) prevented HUVECs from SUL-induced apoptosis. Because of suppression of ectopic PPARdelta by sulindac, adenoviral PPARdelta transduction failed to restore 14-3-3epsilon or prevent PPAR cleavage. Our findings suggest that NSAIDs, but not aspirin (<1 mM) induce endothelial apoptosis via suppression of PPARdelta-mediated 14-3-3epsilon expression.
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PMID:Nonsteroidal anti-inflammatory drugs induced endothelial apoptosis by perturbing peroxisome proliferator-activated receptor-delta transcriptional pathway. 1867 19

Poly (ADP-ribose) polymerase (PARP) has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion (I/R) injury. However, the mechanisms of PARP-mediated heart I/R injury in vivo are still not thoroughly understood. Therefore, in this study, we investigate the effect of PARP inhibition on heart I/R injury and try to elucidate the underlying mechanisms. Studies were performed with I/R rats' hearts in vivo. Ischaemia followed by reperfusion caused a significant increase in Poly (ADP-ribose) (PAR), c-Jun NH2-terminal kinase (JNK) and apoptosis-inducing factor (AIF) activity. Administration of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ), an inhibitor of PARP, decreased myocardial infarction size from 61.11+/-7.46%[0] to 38.83+/-5.67% (P<0.05) and cells apoptosis from 35+/-5.3% to 20+/-4.1% (P<0.05) and simultaneously improved the cardiac function. Western blot analysis showed that administration of DPQ reduced the activation of JNK and attenuated mitochondrial-nuclear translocation of AIF. Additionally, administration of SP600125, an inhibitor of JNK, attenuated mitochondrial-nuclear translocation of AIF. The results of the present study demonstrated that the inhibition of PARP was able to reduce heart I/R injury in vivo. Our results also suggested that JNK may be downstream of PARP activation and be required for PARP-mediated AIF translocation. Inhibition of the activity of PARP may reduce heart I/R injury via suppressing AIF translocation mediated by JNK.
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PMID:Inhibition of the activity of poly (ADP-ribose) polymerase reduces heart ischaemia/reperfusion injury via suppressing JNK-mediated AIF translocation. 1878 86

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.
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PMID:Effect of L-2286, a poly(ADP-ribose)polymerase inhibitor and enalapril on myocardial remodeling and heart failure. 1880 6

Blocking of poly(ADP-ribose) polymerase (PARP)-1 has been expected to protect the heart from ischemia-reperfusion injury. We have recently identified a novel and orally active PARP-1 inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl)-methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], and its major metabolite, KR-34285 [2-[carboxy(4-methoxyphenyl)methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide]. KR-33889 potently inhibited PARP-1 activity with an IC(50) value of 0.52 +/- 0.10 microM. In H9c2 myocardial cells, KR-33889 (0.03-30 microM) showed a resistance to hydrogen peroxide (2 mM)-mediated oxidative insult and significantly attenuated activation of intracellular PARP-1. In anesthetized rats subjected to 30 min of coronary occlusion and 3 h of reperfusion, KR-33889 (0.3-3 mg/kg i.v.) dose-dependently reduced myocardial infarct size. KR-34285, a major metabolite of KR-33889, exerted similar patterns to the parent compound with equi- or weaker potency in the same studies described above. In separate experiments for the therapeutic time window study, KR-33889 (3 mg/kg i.v.) given at preischemia, at reperfusion or in both, in rat models also significantly reduced the myocardial infarction compared with their respective vehicle-treated group. Furthermore, the oral administration of KR-33889 (1-10 mg/kg p.o.) at 1 h before occlusion significantly reduced myocardial injury. The ability of KR-33889 to inhibit PARP in the rat model of ischemic heart was confirmed by immunohistochemical detection of poly(ADP-ribose) activation. These results indicate that the novel PARP inhibitor KR-33889 exerts its cardioprotective effect in in vitro and in vivo studies of myocardial ischemia via potent PARP inhibition and also suggest that KR-33889 could be an attractive therapeutic candidate with oral activity for several cardiovascular disorders, including myocardial infarction.
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PMID:A novel and orally active poly(ADP-ribose) polymerase inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl) methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], attenuates injury in in vitro model of cell death and in vivo model of cardiac ischemia. 1883 68

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein best known to facilitate DNA base excision repair. Recent work has expanded the physiologic functions of PARP-1, and it is clear that the full range of biologic actions of this important protein are not yet fully understood. Regulation of the product of PARP-1, poly(ADP-ribose) (PAR), is a dynamic process with PAR glycohydrolase playing the major role in the degradation of the polymer. Under pathophysiologic situations overactivation of PARP-1 results in unregulated PAR synthesis and widespread neuronal cell death. Once thought to be necrotic cell death resulting from energy failure, we have found that PARP-1-dependent cell death is dependent on the generation of PAR, which triggers the nuclear translocation of apoptosis-inducing factor resulting in caspase-independent cell death. This form of cell death is distinct from apoptosis, necrosis, or autophagy and is termed parthanatos. PARP-1-dependent cell death has been implicated in tissues throughout the body and in diseases afflicting hundreds of millions worldwide, including stroke, Parkinson's disease, heart attack, diabetes, and ischemia reperfusion injury in numerous tissues. The breadth of indications for PARP-1 injury make parthanatos a clinically important form of cell death to understand and control.
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PMID:Mitochondrial and nuclear cross talk in cell death: parthanatos. 1907 45

Niacin (vitamin B(3)) is required to form nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are involved in scores of anabolic and catabolic redox reactions throughout metabolism. It is now understood that NAD(+) is also a substrate for several families of ADP-ribosylation reactions, which control processes like DNA repair, replication and transcription, the activity of G-proteins, chromatin structure and intracellular calcium signalling. Poly(ADP-ribose)polymerase-1 (PARP-1) is the most active of the PARP enzymes, and it has been implicated in both prevention and aggravation of disease processes. Inhibition of poly-ADP-ribose formation will tend to cause genomic instability and tumorigenesis in chronic models of DNA damage, but the same inhibition can prevent many acute disease processes, such as stroke, myocardial infarction and septic shock. In models of acute stress, PARP-1 inhibition may protect cellular NAD pools and prevent nuclear factor-kappaB-dependent inflammatory signalling, while long-term protective roles for PARP-1 include DNA repair and regulation of chromatin structure. Promising new PARP-1 inhibitors may display interactions with dietary niacin status and may have long-term deleterious effects on genomic stability, but may be extremely valuable for the treatment of acute inflammatory conditions.
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PMID:Poly ADP-ribose polymerase-1 and health. 2046 95

Poly(ADP-ribose) polymerases (PARPs) are a family of cell signaling enzymes present in eukaryotes, which are involved in the poly(ADP-ribosylation) of DNA binding proteins. While an 18 member superfamily of PARPs has been identified, however PARP-1 the most abundant isoform accounts for more than 90% of its functions. PARP-1 works as DNA damage nick sensor, which uses NAD(+) to form polymers of ADP-ribose (PAR) and nicotinamide. Three consequences of the activation of PARP-1 are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of proinflammatory genes. Consequently, pharmacological inhibition of PARP has the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). Through this article we have tried to develop a brief and simplified picture of the principal physiological and pathophysiological roles governed by PARP-1 and its therapeutic implications.
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PMID:Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications. 2063 99

Parthanatos is a form of cell death, which often occurs in many diseases such as stroke, Parkinson's disease, heart attack, diabetes, and ischemia reperfusion injury. In a cell, the activation of PARP-1 caused by excitotoxicity leads to Parthanatos, which is also known as PARP-1-dependent cell death. There are multiple cell signaling pathways involved in the process of Parthanatos, which have not been fully understood. The main focus of this article is underlying molecular mechanisms of Parthanatos.
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PMID:[A new form of cell death: Parthanatos]. 2087 Jun 8


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