Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice.
Ageing
Endothelium
Hutchinson-Gilford progeria syndrome
Journal
European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263
Informations de publication
Date de publication:
07 11 2021
07 11 2021
Historique:
received:
05
12
2020
revised:
29
03
2021
accepted:
12
08
2021
pubmed:
15
8
2021
medline:
18
11
2021
entrez:
14
8
2021
Statut:
ppublish
Résumé
Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, increased expression of inflammatory markers, DNA damage, and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular ageing. We generated ECs from iPSCs belonging to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage, and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acetylated low-density lipoprotein uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects that may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1). Progeria mice treated with mTERT lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice. Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases.
Identifiants
pubmed: 34389865
pii: 6352231
doi: 10.1093/eurheartj/ehab547
pmc: PMC8603239
doi:
Substances chimiques
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4352-4369Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL133254
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148338
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
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