VCAM-1 accelerates atrial remodeling in TERT-/- mice

Abstract

Abstract Background Aging, an independent risk factor for AF, could significantly increase its morbidity and mortality. The mechanism of AF in the elderly population remains to be further elucidated. Atrial remodeling is considered to be an important mechanism of atrial fibrillation. Telomerase dysfunction and telomere shortening are important signs of aging, and the relationship and mechanism between telomerase dysfunction and atrial remodeling is not very clear. Purpose This study aims to explore the mechanism of atrial remodeling caused by telomerase dysfunction. Methods The atrial electrophysiology was used to detect refractory period (ERP) and atrial fibrillation inducibility, and the epicardial electrical mapping technique was used to detect the atrial conduction velocity, direction and conduction heterogeneity to evaluate the atrial electrical remodeling. HE and Masson staining were used to evaluate atrial structural remodeling. RNA-seq analysis screened out the differential genes and corresponding pathways in each model. Results Compared with wild-type (WT) mice, a third-generation of telomerase reverse-transcriptase knockout mice (F3 TERT-/-, hereafter as TERT-/-) showed a shortened atrial ERP, increased atrial fibrillation inducibility, slowed atrial conduction velocity,change in the direction of propagation, and increased atrial fibrosis, suggesting electrical and structural remodeling in TERT-/- mice. RNA-seq revealed significant changes in cell adhesion molecules (CAMs) of TERT-/- mice compared with the WT, among which vascular adhesion molecule (VCAM-1) changed most significantly. Then, TERT-/- mice were treated with anti-VCAM-1 neutralizing antibodies, atrial electrical and structural remodeling was partially relieved compared to untreated TERT-/- mice. RNA-seq and KEGG enrichment analysis were conducted on differential genes, which were mainly concentrated on extracellular matrix (ECM)-receptor interaction. Furthermore, we found that the extracellular matrix LAMC3, Collgen1 and myofibroblast marker α-SMA were reversed in TERT-/- mice treated with anti-VCAM-1 neutralizing antibodies compared with TERT-/- mice. Conclusion VCAM-1 could accelerate the production of extracellular matrix, and ultimately lead to atrial electricity and structural remodeling, and the occurrence of atrial fibrillation in TERT-/- mice.