Salidroside treatment decreases the susceptibility of atrial fibrillation in diabetic mice by reducing mTOR-STAT3-MCP-1 signaling and atrial inflammation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinic, and type 2 diabetes mellitus (T2DM) is an independent risk factor for AF. Salidroside (Sal), the active ingredient of the Rhodiola rosea, has hypoglycemic, anti-inflammatory, anti-fibrotic and anti-arrhythmic effects. The aim of this study is to investigate the effects and underlying molecular mechanisms of Sal on T2DM associated atrial inflammation and the pathogenesis of AF. In the in vivo study, T2DM mice model was established by high-fat diet and intraperitoneal injection of streptozotocin (STZ). Sal (25 mg/kg/d, 50 mg/kg/d, and 100 mg/kg/d) was administered orally for 4 weeks. T2DM caused atrial electrical and structural remodeling and significantly increased the susceptibility of AF. Meanwhile, mTOR-STAT3-MCP-1 signaling and inflammatory markers were also significantly enhanced in diabetic atria. However, Sal dose-dependently ameliorated cardiac dysfunction, mitigated atrial structural and electrical remodeling, and reduced atrial inflammation. Moreover, Sal-treated group exhibited remarkably down-regulated activity of mTOR-STAT3-MCP-1 pathway, and decreased atrial monocyte/macrophage infiltration. In palmitic acid (PA)-challenged HL-1 cells, Sal attenuated cytotoxicity, downregulated the expressions of TNF-α, IL-6, MCP-1, and inhibited the activation of mTOR-STAT3 signaling. However, co-treatment with MHY1485 (a mTOR agonist) reversed these effects. Taken together, the present study demonstrates that Sal treatment decreases the susceptibility of AF in diabetic mice by reducing mTOR-STAT3-MCP-1 signaling and atrial monocyte/macrophage infiltration. Sal treatment may represent a novel preventive therapy for cardiac arrhythmia and atrial fibrillation in diabetic patients.