Upregulation of SIRT1 Contributes to dmPGE2-dependent Radioprotection of Hematopoietic Stem Cells.

Autor: Liu L; Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN, 46202, USA., Li H; Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN, 46202, USA., Patterson AM; Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN, 46202, USA.; Department of Medicine/Hematology Oncology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA., Plett PA; Department of Medicine/Hematology Oncology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA., Sampson CH; Department of Medicine/Hematology Oncology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA., Mohammad KS; Department of Medicine/Endocrinology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA., Capitano ML; Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN, 46202, USA., Singh P; Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN, 46202, USA.; Department of Medicine/Hematology Oncology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA., Yao C; Shanghai Municipal Hospital of Traditional Chinese Medicine, NO.274, middle Zhijiang Road, Shanghai, China., Orschell CM; Department of Medicine/Hematology Oncology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA. corschel@iupui.edu., Pelus LM; Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN, 46202, USA. lpelus@iupui.edu.; Department of Medicine/Hematology Oncology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA. lpelus@iupui.edu.
Jazyk: angličtina
Zdroj: Stem cell reviews and reports [Stem Cell Rev Rep] 2022 Apr; Vol. 18 (4), pp. 1478-1494. Date of Electronic Publication: 2022 Mar 23.
DOI: 10.1007/s12015-022-10368-2
Abstrakt: Exposure to potentially lethal high-dose ionizing radiation results in bone marrow suppression, known as the hematopoietic acute radiation syndrome (H-ARS), which can lead to pancytopenia and possible death from hemorrhage or infection. Medical countermeasures to protect from or mitigate the effects of radiation exposure are an ongoing medical need. We recently reported that 16,16 dimethyl prostaglandin E 2 (dmPGE 2 ) given prior to lethal irradiation protects hematopoietic stem (HSCs) and progenitor (HPCs) cells and accelerates hematopoietic recovery by attenuating mitochondrial compromise, DNA damage, apoptosis, and senescence. However, molecular mechanisms responsible for the radioprotective effects of dmPGE 2 on HSCs are not well understood. In this report, we identify a crucial role for the NAD + -dependent histone deacetylase Sirtuin 1 (Sirt1) downstream of PKA and CREB in dmPGE 2 -dependent radioprotection of hematopoietic cells. We found that dmPGE 2 increases Sirt1 expression and activity in hematopoietic cells including HSCs and pharmacologic and genetic suppression of Sirt1 attenuates the radioprotective effects of dmPGE 2 on HSC and HPC function and its ability to reduce DNA damage, apoptosis, and senescence and stimulate autophagy in HSCs. DmPGE 2 -mediated enhancement of Sirt1 activity in irradiated mice is accompanied by epigenetic downregulation of p53 activation and inhibition of H3K9 and H4K16 acetylation at the promoters of the genes involved in DNA repair, apoptosis, and autophagy, including p53, Ku70, Ku80, LC3b, ATG7, and NF-κB. These studies expand our understanding of intracellular events that are induced by IR but prevented/attenuated by dmPGE 2 and suggest that modulation of Sirt1 activity may facilitate hematopoietic recovery following hematopoietic stress. Graphical Abstract.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
Externí odkaz: