Role of angiopoietin-like protein 2 in atrial fibrosis induced by human epicardial adipose tissue: Analysis using an organo-culture system

Background We have recently reported that peri-left atrial epicardial adipose tissue (EAT) is associated with atrial myocardial fibrosis, in which angiopoietin-like protein 2 (Angptl2) protein content in EAT is associated with atrial myocardial fibrosis. Objective This study aimed to examine whether Angptl2 contained in peri-left atrial EAT can induce atrial myocardial fibrosis. Methods Human peri-left atrial EAT and abdominal subcutaneous adipose tissue (SAT) were collected from 9 autopsy cases. EAT- or SAT-conditioned medium was dropped onto the rat left atrial epicardial surface using an organo-culture system. Conditioned medium, recombinant Angptl2, and its antibody effects on organo-cultured rat atrial myocardial fibrosis were evaluated. Angptl2 effects on cultured neonatal rat fibroblasts were also investigated. Results EAT-conditioned medium induced atrial fibrosis in organo-cultured rat atrium with a progressive increase in the number of myofibroblasts. The profibrotic effect of EAT was greater than that of SAT. EAT in patients with atrial fibrillation induced a more significant atrial fibrosis than in those without. Treatment with human recombinant Angptl2 induced fibrosis in organo-cultured rat atrium, which was suppressed by the concomitant treatment with Angptl2 antibody. In cultured fibroblasts, Angptl2 upregulated the expression of α-smooth muscle actin, transforming growth factor-β1, phospho-extracellular signal-regulated kinase,phospho-inhibitor of κBα, and phospho-p38 mitogen-activated protein kinase. Conclusion This study demonstrated that Angptl2 contained in EAT played a crucial role in EAT-induced inflammatory atrial fibrosis. The results also suggested that antagonizing the expression of Angptl2 in EAT can be a novel therapeutic approach to prevent atrial fibrillation.