Abstract 10546: Role of Leptin Signaling in Pathogenesis of Atrial Fibrosis and Fibrillation
BACKGROUND: It has been reported that metabolic syndrome is associated with increased risk of atrial fibrillation (AF). While leptin regulates energy balance, it also exerts cardiovascular activity, which has not yet fully understood.
OBJECTIVES: Here we tested the hypothesis weather leptin signaling would contribute to atrial fibrosis and AF evoked by the activation of rennin-angiotensin system.
METHOD: 1) Eight weeks old male CL57/B6J controlmice (CNT) and aged-matched ob/ob mice (leptin deficient) were subcutaneously infused with angiotensin II (ATII, 2.0 mg/kg/day) or vehicle (VEH) via an osmotic minipump for two weeks. Transesophageal atrial pacing was preformed to induce AF. 2) Left atrial (LA) fibroblast isolated from adult Sprague-Dawley (SD) rat and Zucker rat (leptin receptor malfunction) were cultured, followed by the addition of leptin (100 ng/ml) or ATII (100nM) for 24 hours.
RESULTS: 1) ob/ob mice had higher levels of blood glucose and serum insulin compared with CNT (p<0.01). Transesophageal pacing induced AF in all the CNT-ATII mice (8/8, 100 %), while it did not induce any AF in other three groups (CNT-VEH, ob/ob-ATII and ob/ob-VEH groups, p<0.01). Masson trichrome staining revealed that continuous ATII infusion caused inhomogeneous interstitial fibrosis in CNT mouse LA (CNT-ATII group). However, ATII infusion did not cause such fibrosis in ob/ob mouse LA (ob/ob-ATII group, p<0.05). 2) In cultured SD rat fibroblasts, both leptin and ATII increased monocyte chemoattractant protein-1 (MCP-1) and α-smooth muscle actin (α-SMA) expression. By comparison, in Zucker fibroblast, neither leptin nor ATII influence MCP-1 expression. In Zucker fibroblast, ATII increased α-SMA while leptin did not influence its expression.
CONCLUSIONS: Our results firstly demonstrated that leptin signaling is indispensable for the development of atrial fibrosis evoked by ATII. The results also suggested that MCP-1 expression was positively regulated by the stimulation of leptin receptor. Because it is reported that serum leptin levels were increased in metabolic syndrome subjects, leptin signaling may be a therapeutic target to prevent atrial fibrosis and AF in this population.
- © 2011 by American Heart Association, Inc.