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

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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.

Authors

Aneesh Bapat, Guoping Li, Ling Xiao, Ashish Yeri, Maarten Hulsmans, Jana Grune, Masahiro Yamazoe, Maximilian J. Schloss, Yoshiko Iwamoto, Justin Tedeschi, Xinyu Yang, Matthias Nahrendorf, Anthony Rosenzweig, Patrick T. Ellinor, Saumya Das, David Milan