Pleiotropic Cellular Functions of PARP1 in Longevity and Aging: Genome Maintenance Meets Inflammation

Mangerich, Aswin; Bürkle, Alexander

doi:10.1155/2012/321653

Cited by 106 publications

(81 citation statements)

References 217 publications

(240 reference statements)

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“…One of these roles includes the activation of the nuclear enzyme poly(ADP-ribose), polymerase (PARP-1), which leads to the production of inflammatory mediators such as iNOS, ICAM-1, and major histocompatibility complex class II. Lack of NO leads to vasodilator dysfunction and promotes endothelial apoptosis, whereas nitrative stress and increased H 2 O 2 levels lead to poly(ADP-ribose) polymerase (PARP)-1 activation, which contributes to NF-B -dependent gene transcription (Ungvari et al, 2010;Mangerich and Burkle, 2012). NF-B, an integral factor in vascular health triad (Donato et al, 2009), is involved in transcriptional activation of pro-inflammatory and pro-oxidative genes leading to impaired vascular function.…”

Section: Nuclear Factor-kappa Bmentioning

confidence: 99%

Oxidized LDL and NO synthesis—Biomarkers of endothelial dysfunction and ageing

Grădinaru

Borșa²,

Ionescu³

et al. 2015

Mechanisms of Ageing and Development

136

103

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Oxidized LDL (oxLDL) and nitric oxide (NO) exert contradictory actions within the vascular endothelium microenvironment influencing key events in atherogenesis. OxLDL and NO are so far regarded as representative parameters of oxidative stress and endothelial dysfunction, new targets in prevention, diagnosis and therapy of cardiovascular diseases, and also as candidate biomarkers in evaluating the human biological age. The aim of this review is to explore recent literature on molecular mechanisms and pathophysiological relationships between LDL oxidation, NO synthesis and vascular endothelium function/dysfunction in ageing, focusing on the following aspects: (1) the impact of metabolic status on both LDL oxidation and NO synthesis in relation with oxidative stress, (2) the use of oxidized LDL and NO activity as biomarkers in human studies reporting on cardiovascular outcomes, and (3) evidences supporting the importance of oxidized LDL and NO activity as relevant biomarkers in vascular ageing and age-related diseases.

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Section: Nuclear Factor-kappa Bmentioning

confidence: 99%

Oxidized LDL and NO synthesis—Biomarkers of endothelial dysfunction and ageing

Grădinaru

Borșa²,

Ionescu³

et al. 2015

Mechanisms of Ageing and Development

136

103

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“…PARP1 [the poly (ADP-ribose) polymerase 1 gene] is a gene that has been linked to longevity in mammals [17]. PARP1 has a key role in regulating cell-cycle and DNA repair mechanisms.…”

Section: Histone Modificationsmentioning

confidence: 99%

Epigenetic Involvement in Hutchinson-Gilford Progeria Syndrome: A Mini-Review

et al. 2014

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disease that leads to a severe premature ageing phenotype, caused by mutations in the LMNA gene. The LMNA gene codes for lamin-A and lamin-C proteins, which are structural components of the nuclear lamina. HGPS is usually caused by a de novo C1824T mutation that leads to the accumulation of a dominant negative form of lamin-A called progerin. Progerin also accumulates physiologically in normal ageing cells as a rare splicing form of lamin-A transcripts. From this perspective, HGPS cells seem to be good candidates for the study of the physiological mechanisms of ageing. Progerin accumulation leads to faster cellular senescence, stem cell depletion and the progeroid phenotype. Tissues of mesodermic origin are especially affected by HGPS. HGPS patients usually have a bad quality of life and, with current treatments, their life expectancy does not exceed their second decade at best. Though progerin can be expressed in almost any tissue, when death occurs, it is usually due to cardiovascular complications. In HGPS, severe epigenetic alterations have been reported. Histone-covalent modifications are radically different from control specimens, with the tendency to lose the bipartition into euchromatin and heterochromatin. This is reflected in an altered spatial compartmentalization and conformation of chromatin within the nucleus. Moreover, it seems that microRNAs and microRNA biosynthesis might play a role in HGPS. Exemplary in this connection is the suggested protective effect of miR-9 on the central nervous system of affected individuals. This mini-review will report on the state of the art of HGPS epigenetics, and there will be a discussion of how epigenetic alterations in HGPS cells can alter the cellular metabolism and lead to the systemic syndrome.

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“…PARP1 is a ubiquitously expressed protein playing key roles in genomic maintenance, chromatin organization, transcription, and the regulation of cell death (Mangerich and Bürkle, 2012;Rouleau et al, 2010). PARP1 binds to DNA strand breaks and by using NAD + as a substrate, catalyzes the formation of homopolymeric branched chains of poly(ADP ribose) (PAR) of different length that are covalently bound to "acceptor" proteins at glutamate, aspartate or lysine residues.…”

Section: Introductionmentioning

confidence: 99%

Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions

et al. 2016

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Biological effects of CEES treated cells are significantly influenced by treatment protocol. Optimized protocol for the treatment of HaCaT cells with CEES. CEES induces a dose and time dependent PARylation response in HaCaT cells. CEES induced PAR formation is predominantly due to the activation of PARP1. Keywords:Poly(ADP-ribose) Poly(ADP-ribose) polymerases Sulfur mustard CEES HaCaT keratinocytes Solvent A B S T R A C T Sulfur mustard (SM) is a bifunctional alkylating agent with a long history of use as a chemical weapon. Although its last military use is dated for the eighties of the last century, a potential use in terroristic attacks against civilians remains a significant threat. Thus, improving medical therapy of mustard exposed individuals is still of particular interest. PARP inhibitors were recently brought into the focus as a potential countermeasure for mustard induced pathologies, supported by the availability of efficient compounds successfully tested in cancer therapy.PARP activation after SM treatment was reported in several cell types and tissues under various conditions; however, a detailed characterization of this phenomenon is still missing. This study provides the basis for such studies by developing and optimizing experimental conditions to investigate poly(ADP ribosyl)ation (PARylation) in HaCaT keratinocytes upon treatment with the monofunctional alkylating agent 2 chloroethyl ethyl sulfide ("half mustard", CEES). By using an immunofluorescence based approach, we show that optimization of experimental conditions with regards to the type of solvent, dilution factors and treatment procedure is essential to obtain a homogenous PAR staining in HaCaT cell cultures. Furthermore, we demonstrate that different CEES treatment protocols significantly influence the cytotoxicity profiles of treated cells. Using an optimized treatment protocol, our data reveals that CEES induces a dose and time dependent dynamic PARylation response in HaCaT cells that could be completely blocked by treating cells with the clinically relevant pharmacological PARP inhibitor ABT888 (also known as veliparib). Finally, siRNA experiments show that CEES induced PAR formation is predominantly due to the activation of PARP1. In conclusion, this study provides a detailed analysis of the CEES induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to study the molecular mechanism of PARP1 activation and its functional consequences after mustard treatment in general.

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Pleiotropic Cellular Functions of PARP1 in Longevity and Aging: Genome Maintenance Meets Inflammation

Cited by 106 publications

References 217 publications

Oxidized LDL and NO synthesis—Biomarkers of endothelial dysfunction and ageing

Oxidized LDL and NO synthesis—Biomarkers of endothelial dysfunction and ageing

Epigenetic Involvement in Hutchinson-Gilford Progeria Syndrome: A Mini-Review

Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions

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