Knockdown of angiopoietin-like 2 induces clearance of vascular endothelial senescent cells by apoptosis, promotes endothelial repair and slows atherogenesis in mice.

Laurie Caland,Louis Villeneuve,Gerardo Ferbeyre,Pauline Labbé,Pierre-Emmanuel Noly,Maya Mamarbachi,Michel Carrier,Éric Thorin,Nathalie Thorin-Trescases

doi:10.18632/aging.102020

Laurie Caland, Louis Villeneuve + Show 7 more

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https://doi.org/10.18632/aging.102020

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Journal: Aging	Publication Date: Jun 11, 2019
Citations: 21	License type: cc-by

Affiliation: Montreal Heart Institute, Université de Montréal

Abstract

Elimination of senescent cells (SnC) is anti-atherogenic, but the specific contribution of senescent vascular endothelial cells (EC) is unknown. We inactivated angiopoietin like-2 (angptl2), a marker of SnEC and a pro-atherogenic cytokine in LDLr-/-, hApoB100+/+ atherosclerotic (ATX) mice. Three months after a single vascular delivery of a small hairpin (sh)Angptl2 in 3-month old ATX mice using an adeno-associated virus serotype 1 (AAV1), aortic atheroma plaque progression was slowed by 58% (p<0.0001). In the native aortic endothelium, angptl2 expression was decreased by 80%, in association with a reduced expression of p21, a cyclin-dependent kinase inhibitor overexpressed in growth-arrested SnC. Endothelial activation was reduced (lower Icam-1, Il-1β and Mcp-1 expression), decreasing monocyte Cd68 expression in the endothelium. One week post-injection, the ratio Bax/Bcl2 increased in the endothelium only, suggesting that angptl2+/p21+ SnEC were eliminated by apoptosis. Four weeks post-injection, the endothelial progenitor marker Cd34 increased, suggesting endothelial repair. In arteries of atherosclerotic patients, we observed a strong correlation between p21 and ANGPTL2 (r=0.727, p=0.0002) confirming the clinical significance of angptl2-associated senescence. Our data suggest that therapeutic down-regulation of vascular angptl2 leads to the clearance of SnEC by apoptosis, stimulates endothelial repair and reduces atherosclerosis.

Highlights

Senescent cells lose their proliferative potential in response to various stresses
Endothelial expression of angptl2 and senescence gene markers parallels atherogenesis Firstly, and as expected, endothelial expression of angptl2, Pai-1 and p21 parallels the growing atheroma plaque in untreated LDLr-/-;hApoB100+/+ atherosclerotic (ATX) mice up to 12-month old (-mo) (Figure 1); p21 is a cyclin-dependent kinase inhibitor overexpressed in growth-arrested senescent cells, and Pai-1 is a recognized senescence-associated secretory phenotype (SASP) member and inducer of senescence [15]
The novel findings of this study are that downregulation of vascular angiopoietin-like 2 (Angptl2) may limit the progression of atherosclerotic lesions in pre-atherosclerotic dyslipidemic mice by 1) inducing clearance of senescent endothelial cells (EC) through apoptosis and 2) by promoting endothelium repair and attenuating the proinflammatory environment in the wall of the aorta

Summary

Introduction

Senescent cells lose their proliferative potential in response to various stresses. They secrete a variety of pro-inflammatory mediators and proteases, gathered in the senescence-associated secretory phenotype (SASP) [1] that engages the immune system to eliminate senescent cells [2, 3]. Senescent cells accumulate in aging organisms, chronic age-related diseases and bening tumors [4,5,6,7]; elimination of senescent cells contributes to improve health [8,9,10,11]. They accumulate in tissues affected by atherosclerosis [1214] and their elimination strikingly reduces atherogenicity in animal models [12, 14]. ABT263, a Bcl family inhibitor, was able to eliminate senescent cells after irradiation in mice and to rejuvenate bone marrow stem cells from both irradiated mice and naturally aged mice [21], to reverse pulmonary fibrosis in a mouse model [22], and to reduce senescence-associated Tau-dependent neuronal damage and cognitive decline [23]

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