Genetic inhibition of serum glucocorticoid kinase 1 prevents obesity-related atrial fibrillation
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
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
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Research Article Cardiology Metabolism

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.

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

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Figure 7

Constitutive SGK1 activation may increase susceptibility to obesity-induced AF.

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Constitutive SGK1 activation may increase susceptibility to obesity-indu...
(A) Lean SGK1 CA and lean WT littermates were studied with electrophysiology studies and optical mapping. (B) Inter-atrial difference in APD50 in SGK1 CA atria. Paired Student’s t test. *P < 0.05. (C) Optical mapping–derived APD90 in right (top) and left (bottom) atria with representative AP tracings. Unpaired Student’s t test. *P < 0.05. (D) SGK1 CA and WT mice were fed an HFD for 6 weeks and then underwent electrophysiologic and biochemical studies. (E) Electrophysiologic assessment of WT and SGK1 CA mice fed HFD for 6 weeks with telemetry for PAC quantification (top left) and invasive electrophysiologic studies to determine AF inducibility (>1 second) (top right), total AF burden during electrophysiology study (bottom left), and total number of AF episodes > 250 ms (bottom right). P values obtained with unpaired Student’s t test for PAC count, Fisher’s exact test for AF inducibility, and Mann-Whitney test for AF burden and frequency. *P < 0.05. (F) Optical mapping–derived APD90 in right (left) and left (right) atria with representative AP tracings. Unpaired Student’s t test. *P < 0.05. (G) qRT-PCR–derived expression of Col1A1 and Nlrp3 atrial tissue. Unpaired Student’s t test. *P < 0.05. Number of mice in each group provided in bar graph or represented by the number of dots in individual figure.