Genetic inhibition of serum glucocorticoid kinase 1 prevents obesity-related atrial fibrillation

Abstract

Obesity is an important risk factor for atrial fibrillation (AF), but a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned within multiple obesity-related pathways, and prior work has shown a pathologic role of SGK1 signaling in ventricular arrhythmias. We validated a mouse model of obesity-related AF using wild-type mice fed a high-fat diet. RNA sequencing of atrial tissue demonstrated substantial differences in gene expression, with enrichment of multiple SGK1-related pathways, and we showed upregulated of SGK1 transcription, activation, and signaling in obese atria. Mice expressing a cardiac specific dominant-negative SGK1 were protected from obesity-related AF, through effects on atrial electrophysiology, action potential characteristics, structural remodeling, inflammation, and sodium current. Overall, this study demonstrates the promise of targeting SGK1 in a mouse model of obesity-related AF.