Dataset Information

PARP1 inhibitor (PJ34) improves the function of aging-induced endothelial progenitor cells by preserving intracellular NAD+ levels and increasing SIRT1 activity.

ABSTRACT: BACKGROUND:Nicotinamide adenine dinucleotide (NAD+) is a critical molecule involved in various biological functions. Poly (ADP-ribose) polymerase 1 (PARP1) and sirtuin 1 (SIRT1) affect cellular NAD+ levels and play essential roles in regulating metabolism. However, there has been little research on the effects of PARP1 and SIRT1 crosstalk during senescence. METHODS:We isolated endothelial progenitor cells (EPCs) from human umbilical cord blood and treated them with a PARP1 inhibitor (PJ34). RESULTS:Using a stress-induced premature aging model built by H2O2, transfection with adenoviral vectors, and Western blot analysis, we observed that PJ34 treatment preserved intracellular NAD+ levels, increased SIRT1 activity, decreased p53 acetylation, and improved the function of stress-induced premature aging EPCs. CONCLUSIONS:Our results suggest that PJ34 improves the function of aging-induced EPCs and may contribute to cellular therapies for atherosclerosis.

SUBMITTER: Zha S

PROVIDER: S-EPMC6107962 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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PARP1 inhibitor (PJ34) improves the function of aging-induced endothelial progenitor cells by preserving intracellular NAD<sup>+</sup> levels and increasing SIRT1 activity.

Zha Siyuan S Li Zhen Z Cao Qing Q Wang Fei F Liu Fang F

Stem cell research & therapy 20180823 1

<h4>Background</h4>Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is a critical molecule involved in various biological functions. Poly (ADP-ribose) polymerase 1 (PARP1) and sirtuin 1 (SIRT1) affect cellular NAD<sup>+</sup> levels and play essential roles in regulating metabolism. However, there has been little research on the effects of PARP1 and SIRT1 crosstalk during senescence.<h4>Methods</h4>We isolated endothelial progenitor cells (EPCs) from human umbilical cord blood and treated the ...[more]

PMID: 30139380

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Project description:Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD+-SIRT1-PGC-1? axis triggered by hyperactivation of the DNA damage sensor PARP1. This phenotype is rescued by PARP1 inhibition or by supplementation with NAD+ precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a novel nuclear-mitochondrial cross-talk that is critical for the maintenance of mitochondrial health. Mice carrying WT, or CX (Csa-/-/Xpa-/-) alleles in a C57BL/6 background were maintained under standard laboratory conditions and allowed free access to water and control casein pelleted diet (Research Diets D12450B). At 3 months of age, 3 replicates of each of the CX and WT mice were given subcutaneous interscapular injections of 500 mg of Nicotinamide riboside/kg body weight/day or the equivalent volume of saline for 14 consecutive days at 4:00 pm. On day 15, the mice were sacrificed and half of the cerebellum was harvested for purification of mitochondria, with the left half snap-frozen, homogenized, and aliquoted for RNA isolation. Total RNA extraction was done using a TRIzol Plus RNA purification kit as per manufacturer’s protocol. Quality and quantity of the total RNA was tested using the Agilent 2100 Bio-Analyzer and RNA 6000 nano kits. The RNA was labeled using the standard Illumina protocol and hybed overnight to Mouse Ref-8 Illumina arrays. The arrays were scanned using the Beadstation 500 X from Illumina.

Dataset Information

PARP1 inhibitor (PJ34) improves the function of aging-induced endothelial progenitor cells by preserving intracellular NAD+ levels and increasing SIRT1 activity.

Publications

PARP1 inhibitor (PJ34) improves the function of aging-induced endothelial progenitor cells by preserving intracellular NAD<sup>+</sup> levels and increasing SIRT1 activity.

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