Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests that nitric oxide (NO) may function as a second messenger in the intracellular signal transduction pathways. We explored the possibility that NO was involved in the signal for triggering apoptosis in smooth muscle cells (SMCs). Chemical NO donors induced SMCs apoptosis in a concentration- and time-dependent manner. The membrane-permeable cGMP analogue, dibutyryl-cGMP, did not induce SMCs apoptosis, and the highly selective inhibitor of cGMP-dependent protein kinase, KT5823, was unable to inhibit the induction of NO-induced SMCs apoptosis. Inhibitor of ADP-ribosyltransferase slightly attenuated the induction of SMCs apoptosis by S-nitroso-N-acetyl penicillamine (SNAP). The inhibitor of Na+-H+ antiporter, amiloride, completely inhibited the induction of SMCs apoptosis by SNAP. These results demonstrate for the first time that NO can induce apoptosis in SMCs, suggesting that NO acts as a mediator in the development of atherosclerosis lesion via alterations in the number of SMCs. In addition, the results suggest that NO exert these effects through a pathway that does not involve guanylate cyclase and cGMP-dependent protein kinase.
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PMID:Nitric oxide donor SNAP induces apoptosis in smooth muscle cells through cGMP-independent mechanism. 866 Mar 29

Nitric oxide (NO) and its reactant product, peroxynitrite, have been implied to mediate neuronal damage following cerebral ischemia. However, the cellular targets of these compounds remain unclear. Studies using poly(ADP-ribose) polymerase (PARP) inhibitors and PARP knock-out mice have recently demonstrated that excessive activation of this nuclear enzyme plays an important role in NO-induced neurotoxicity. To evaluate the relevance of this plausible candidate gene to human stroke, we undertook a case-control study in Japanese. Participants comprised 213 cerebral infarction cases and 374 age- and sex-matched controls. As a primary investigation, we screened polymorphic sites of the PARP gene, and newly identified a total of four polymorphisms in 1230-bp 5'-flanking sequence. None of them were, however, located on the known promoter components of the gene. Two bi-allelic polymorphisms selected and a CA-repeat polymorphism were subsequently characterized in the case-control study, but none were significantly associated with cerebral infarction in the present study. Our data thus suggest that the tested PARP polymorphisms do not principally contribute to cerebral infarction, although extensive searches would be required to clarify whether the PARP gene plays an important role in the pathogenesis of human stroke.
Atherosclerosis 2000 Feb
PMID:Evaluation of the poly(ADP-ribose) polymerase gene in human stroke. 1065 71

Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent single-strand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-kappaB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.
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PMID:Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. 1113 24

Apoptosis is a cell suicide program characterized by distinct morphological (cell shrinkage, membrane blebbing, pyknosis, chromatin margination, denser cytoplasmic images) and biochemical (e.g., DNA fragmentation into distinct ladders; degradation of apoptotic markers such as PARP and nuclear lamins) features. It is involved in multiple physiological processes examplified by involution of mammary tissues, embryonic development, homeostatic maintenance of tissues and organs, and maturation of the immune system, as well as in many pathological conditions represented by neurologic degeneration (Alzeimer's disease), autoimmune and inflammatory diseases, etiology of atherosclerosis, AIDS, and oncogenesis and tumor progression. Numerous molecular entities have been shown to regulate the apoptotic process. This review provides a concise summary of the recent data on the role of oncogenes/tumor suppressor genes, cytokines and growth factors/growth factor receptors, intracellular signal transducers, cell cycle regulators, reactive oxygen species or other free radicals, extracellular matrix regulators/cell adhesion molecules, and specific endonucleases and cytoplasmic proteases (the ICE family proteins) in regulating cell survival and apoptosis. Elucidation of the molecular mechanisms regulating apoptosis bears tremendous impact on enhancing our understanding of many diseases inflicting the human beings and undoubtedly brings us hope for the cure of these diseases.
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PMID:Apoptosis: A Current Molecular Analysis. 1117 95

Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of endothelial dysfunction associated with atherosclerosis, hypertension and aging. Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury and circulatory shock. Here we investigated the role of PARP activation in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension and aging. Retired breeder spontaneously hypertensive rats (SHR, 40 weeks old) and apolipoprotein E knockout mice (apoE-Ko, 10 weeks old) were treated for 20 weeks with vehicle or the potent PARP inhibitor PJ34. In the vehicle-treated SHR rats and apoE-Ko mice (kept on atherogenic diet) there was a significant loss of endothelial function, as measured by the relaxant responsiveness of vascular rings to acetylcholine. SHR rats also developed severe hypertension and cardiac hypertrophy. Treatment with the PARP inhibitor did not influence high blood pressure and cardiac hypertrophy in SHR rats, but it improved Ach-induced, NO-mediated vascular relaxation. In addition to the beneficial effects of chronic treatment with PARP inhibitor, 1-h in vitro incubation of aortic rings from SHR rats with PJ34 (3 micromol/l) was also able to improve the endothelial dysfunction. In contrast, in apoE-Ko mice PJ34 treatment did not affect the parameters studied. Thus, PARP activation contributes to the pathogenesis of endothelial dysfunction associated with hypertension and aging, but not in the current experimental model of atherosclerosis.
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PMID:Activation of poly(ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging. 1201 85

Among oxysterols oxidized at C7 (7alpha-, 7beta-hydroxycholesterol, and 7-ketocholesterol) 7beta-hydroxycholesterol and 7-ketocholesterol are potent inducers of cell death and probably play central roles in atherosclerosis. As suggested by our previous investigations, 7-ketocholesterol might be a causative agent of vascular damage by inducing apoptosis and enhancing superoxide anion (O2*-) production. To determine the precise relationships between cytotoxicity and oxidative stress, the ability of oxysterols oxidized at C7 to induce apoptosis, to stimulate O2*- production and to promote lipid peroxidation was compared with different pro-apoptotic chemicals: antitumoral drugs (VB, Ara-C, CHX, and VP-16) and STS. All compounds, except 7alpha-hydroxycholesterol, induced apoptosis characterized by the occurrence of cells with fragmented and/or condensed nuclei, loss of mitochondrial potential, caspase-3 activation, PARP degradation, and internucleosomal DNA fragmentation. The highest proportion of apoptotic cells was found with antitumoral drugs and STS, whereas the highest overproduction of O2*- detected before and after the loss of mitochondrial potential was obtained with 7beta-hydroxycholesterol and 7-ketocholesterol. Overproduction of O2*- was always correlated with enhanced lipid peroxidation. Vit E was only capable to significantly counteract apoptosis and oxidative stress induced by 7beta-hydroxycholesterol, 7-ketocholesterol, VB and STS. By electron and fluorescence microscopy, myelin figures evocating autophagic vacuoles were barely observed under treatment with 7beta-hydroxycholesterol and 7-ketocholesterol, and their formation occurring before the loss of mitochondrial potential was reduced by Vit E. In the presence of 7alpha-hydroxycholesterol, no enhancement of O2*- production, no lipid peroxidation, and no formation of myelin figures were observed. Collectively, our data demonstrate, that there can be a more or less important stimulation of oxidative stress during apoptosis. They also suggest that enhancement of O2*- production associated with lipid peroxidation during 7beta-hydroxycholesterol and 7-ketocholesterol-induced apoptosis could contribute to in vivo vascular injury, and that myelin figures could constitute suitable markers of oxysterol-induced cell death.
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PMID:Analysis of oxidative processes and of myelin figures formation before and after the loss of mitochondrial transmembrane potential during 7beta-hydroxycholesterol and 7-ketocholesterol-induced apoptosis: comparison with various pro-apoptotic chemicals. 1214 5

Two phenotypes of rat carotid arterial smooth muscle cells (SMC) have been isolated in our laboratory, and their proteolytic and anti-proteolytic activities have been investigated in the presence or absence of various stimulating agents. We report here a comparative study of the cytotoxic effects of nitric oxide (NO) donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP), towards the swirling-type and the epithelioid-type SMCs. The concentration- and time-dependence of NO donors' capacity to induce cell deaths was measured by an intracellular acid phosphatase activity assay and cell counting. The typical morphological features of apoptosis, such as cell blebbing and cytoplasm condensation, were observed by phase contrast microscopy and with a fluorescent DNA-binding dye. Apoptotic cell deaths were confirmed using DNA fragmentation and terminal deoxyribonucelotidyl transferase-mediated dUTP nick end labelling (TUNEL) methods. Western blots were used to investigate the protein expression of several known mediators of apoptosis. It was found that both NO donors induced cell deaths in the SMC phenotypes. Compared to the swirling SMCs, the epithelioid SMCs were much more sensitive to these agents. A time- and dose-dependent decrease of cell viability was observed at NO donor concentrations higher than 0.2 mmol/l. Microscopic methods revealed cell morphology of apoptotic cell deaths. The 180-bp DNA multimers typical of apoptosis were shown by DNA fragmentation. TUNEL technique confirmed that apoptosis occurred most readily in the epithelioid SMCs than the swirling SMCs. When epithelioid SMCs were treated with SNP, changes in p53, p21(WAF1), Bcl-2, caspase 3 and PARP protein expression were found. These protein levels were unchanged when swirling SMCs were similarly treated.
Atherosclerosis 2003 Feb
PMID:Cytotoxicity of nitric oxide donors in smooth muscle cells is dependent on phenotype, and mainly due to apoptosis. 1253 34

Oxidized low-density lipoprotein (oxLDL) is known to induce apoptosis in endothelial cells, and this is believed to contribute to the progression of atherosclerosis. In the present study we made the novel observation that oxLDL-induced death of HMEC-1 cells is accompanied by activation of calpain. The mu-calpain inhibitor PD 151746 decreased oxLDL-induced cytotoxicity, whereas the general caspase inhibitor BAF (t-butoxycarbonyl-Asp-methoxyfluoromethylketone) had no effect. Also, oxLDL provoked calpain-dependent proteolysis of cytoskeletal alpha-fodrin in the HMEC-1 cells. Our observation of an autoproteolytic cleavage of the 80 kDa subunit of mu-calpain provided further evidence for an oxLDL-induced stimulation of calpain activity. The Bcl-2 protein Bid was also cleaved during oxLDL-elicited cell death, and this was prevented by calpain inhibitors, but not by inhibitors of cathepsin B and caspases. Treating the HMEC-1 cells with oxLDL did not result in detectable activation of procaspase 3 or cleavage of PARP [poly(ADP-ribose) polymerase], but it did cause polyubiquitination of caspase 3, indicating inactivation and possible degradation of this protease. Despite the lack of caspase 3 activation, oxLDL treatment led to the formation of nucleosomal DNA fragments characteristic of apoptosis. These novel results show that oxLDL initiates a calpain-mediated death-signalling pathway in endothelial cells.
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PMID:Oxidized low-density lipoprotein induces calpain-dependent cell death and ubiquitination of caspase 3 in HMEC-1 endothelial cells. 1277 16

Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension, and aging. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury, circulatory shock, and aging. Here, we investigated the effect of a new PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction associated with advanced aging using Millar's new Aria pressure-volume conductance system and isolated aortic rings. Young adult (3 months old) and aging (24 months old) Fischer rats were treated for 2 months with vehicle, or the potent PARP inhibitor INO-1001. In the vehicle-treated aging animals, there was a marked reduction of both systolic and diastolic cardiac function and loss of endothelial relaxant responsiveness of aortic rings to acetylcholine. Treatment with INO-1001 improved cardiac performance in aging animals and also acetylcholine-induced, nitric oxide-mediated vascular relaxation. Thus, pharmacological inhibition of PARP may represent a novel approach to improve cardiac and vascular dysfunction associated with aging.
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PMID:A new, potent poly(ADP-ribose) polymerase inhibitor improves cardiac and vascular dysfunction associated with advanced aging. 1521 49

The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors activated by specific ligands. PPARs play an important role in carcinogenesis, inflammation, atherosclerosis, lipid metabolism and diabetes. There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest, apoptosis and induction of differentiation, although the detailed signalling pathways have not been completely elucidated to date. The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability, proliferation, differentiation, apoptosis and expression of some cell cycle related proteins in glial tumor cell lines. The study was performed on human glioblastoma cell lines U-87 MG, T98G, A172 and U-118 MG. Cell lines were treated by ligands of PPARalpha (bezafibrate, gemfibrozil) and PPARgamma (ciglitazone). MTT, flow cytometry, TUNEL assay and immunoblotting were used for detection of changes in cell viability, proliferation, differentiation and apoptosis. Bezafibrate, ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines. The synthetic ligands significantly reduced or induced the expression of cyclins, p27Kip1, p21Waf1/Cip1, MDM-2, Bcl-2, Bax, PARP, Caspase 3, androgen receptors, etc. and did not affect the expression of the differentiation marker GFAP. Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial. Apart from hypolipidemic and hypoglycaemic effects, PPAR ligands may also have significant cytostatic effects of potential use in anticancer treatment.
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PMID:Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors. 1580 Jul 11


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