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

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.

Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

“…p < 0.01, log-rank/Mantel-Cox test. The age at 50% survival (median survival) is indicated next to each graph (d, days) extrinsic mechanisms contribute to hypertrophy of cardiac tissue (Sun et al, 2020), an hypothesis supported by our results.…”

“…However, we focused on tissue morphology and were able to demonstrate improvement of aorta lesions, including smooth muscle cell loss, and amelioration of cardiomyocyte hypertrophy in myocardium from tocilizumab‐treated mice. Hypertrophy of myocardium was previously observed in mouse models expressing endothelium‐targeted progerin (Osmanagic‐Myers et al, 2019; Sun et al, 2020). As SASP activation including IL6 hypersecretion was determined in one of those progeroid mouse strains, it is likely that cell extrinsic mechanisms contribute to hypertrophy of cardiac tissue (Sun et al, 2020), an hypothesis supported by our results.…”

“…Progerin effects on the secretome have been observed in several preclinical models of HGPS (Gonzalo & Coll‐Bonfill, 2019; Kreienkamp et al, 2018; Osmanagic‐Myers et al, 2019; Osorio et al, 2012). In mice, it has been demonstrated that selective expression of progerin in endothelial cells causes dysregulation of circulating molecules and a condition leading to paracrine and profibrotic effects (Osmanagic‐Myers et al, 2019; Sun et al, 2020). Activation of the senescence‐associated secretory phenotype (SASP) by endothelium‐targeted progerin affected most mouse tissues and induced premature aging in the whole organism (Sun et al, 2020).…”

“…In mice, it has been demonstrated that selective expression of progerin in endothelial cells causes dysregulation of circulating molecules and a condition leading to paracrine and profibrotic effects (Osmanagic-Myers et al, 2019;Sun et al, 2020). Activation of the senescence-associated secretory phenotype (SASP) by endothelium-targeted progerin affected most mouse tissues and induced premature aging in the whole organism (Sun et al, 2020). Systemic effects linked to aberrant NF-kB signaling and interleukin 6 (IL6) increase have been observed in Lmna G609G/G609G and Zmpste24 −/− progeroid mice featuring progerin or prelamin A accumulation, while anti-inflammatory drugs have been shown to extend life span (Osorio et al, 2011(Osorio et al, , 2012.…”

Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency

“…Post-mortem analysis of very low numbers of patients has identified end-stage cardiovascular pathologies; however, the study of disease mechanisms requires in vitro and in vivo models of HGPS. Several animal models of HGPS have been reported, including mice with systemic and tissue-restricted progerin expression [ 13 , 14 , 17 , 18 , 19 , 20 , 21 ] and a pig HGPS model [ 22 ]. Most models, at least to some extent, exhibit structural abnormalities in the arterial wall; however, progeriod animal models without additional genetic modifications to alter lipid metabolism lacked atherosclerotic disease, indicating that progerin expression in the absence of pro-atherogenic conditions is not sufficient to induce atheroma plaque formation.…”