Vascular endothelium-targeted Sirt7 gene therapy rejuvenates blood vessels and extends life span in a Hutchinson-Gilford progeria model

Science Advances
Shimin SunBaohua Liu

Abstract

Vascular dysfunction is a typical characteristic of aging, but its contributing roles to systemic aging and the therapeutic potential are lacking experimental evidence. Here, we generated a knock-in mouse model with the causative Hutchinson-Gilford progeria syndrome (HGPS) LmnaG609G mutation, called progerin. The Lmnaf/f ;TC mice with progerin expression induced by Tie2-Cre exhibit defective microvasculature and neovascularization, accelerated aging, and shortened life span. Single-cell transcriptomic analysis of murine lung endothelial cells revealed a substantial up-regulation of inflammatory response. Molecularly, progerin interacts and destabilizes deacylase Sirt7; ectopic expression of Sirt7 alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endothelium-targeted Sirt7 gene therapy, driven by an ICAM2 promoter, improves neovascularization, ameliorates aging features, and extends life span in Lmnaf/f ;TC mice. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.

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Citations

Aug 11, 2020·Current Opinion in Lipidology·Apurba ChakrabartiNadia R Sutton
Jan 5, 2021·Aging Cell·Stefano SquarzoniGiovanna Lattanzi
May 15, 2021·Life Sciences·Alejandra Zúñiga-MuñozMabel Buelna-Chontal
Jun 29, 2021·Frontiers in Cardiovascular Medicine·Mengxia Fu, Jiangping Song
Aug 15, 2021·European Heart Journal·Anahita MojiriJohn P Cooke

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Methods Mentioned

BETA
fluorescence-activated cell sorting
FACS
PCR
co-immunoprecipitation
confocal microscopy
fluorescence microscopy
transgenic

Software Mentioned

STAR
Cell Ranger
DAVID

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