CXCL12 Inhibition Prevents Telomere Shortening and Repression of Telomerase Activity in Both Early and Late Post-menopausal Atherosclerosis via ABCA1 Upregulation

Abstract

Vascular senescence is a key component in the initiation of atherosclerosis and its related cardiovascular disorders. C-X-C Motif Chemokine Ligand 12 (CXCL12), the CXC chemokine receptor 4 (CXCR4) ligand is a chemokine known to promote atherosclerosis. However, the role of telomeres in CXCL12-mediated senescence-induced atherosclerosis remains obscure. This study aimed to unravel the role of CXCL12 and its association with telomeres in the context of menopause-induced arterial senescence and atherosclerosis. Apoe–/– mice underwent bilateral ovariectomy (OVX) to simulate early and late postmenopausal (EPM) conditions (1 and 5 weeks post-OVX, respectively). POL5551, a selective CXCR4 antagonist, was administered as a continuous infusion (30 mg/kg/day in PBS) using a subcutaneously implanted osmotic minipump for two weeks. ATP binding cassette transporter A1 (ABCA1), a cholesterol efflux regulator was significantly downmodulated (p < 0.05), while NOD-, LRR- and pyrin domain-containing protein 3 (NLR) family pyrin domain containing 3 (NLRP3), inducible nitric oxide synthase (iNOS) and the inflammatory mediators were considerably enhanced (p < 0.05) in both EPM and LPM mice groups. Notably, atherosclerosis was more prominent in the EPM than in the LPM mice. However, POL5551 treatment effectively ameliorated the reduced ABCA1 expression and the increased inflammatory response. Hence, we propose that inhibition of CXCL12 proffers robust anti-senescent and anti-atherosclerotic effects.