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 1

Diet-induced obesity results in increased AF inducibility and is associated with upregulation of SGK1 signaling.

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Diet-induced obesity results in increased AF inducibility and is associa...
(A) Schematic of HFD feeding in WT mice to generate obese WT mice. IPGTT, intraperitoneal glucose tolerance testing. (B) Glucose levels after glucose tolerance test in lean and obese mice. (C) AF inducibility in lean and obese mice after specified period of feeding control or HFD chow. (D) Heatmap derived from RNA-sequencing data demonstrating GSEA core enriched genes in SGK1-related pathways (FWER P < 0.05) that are differentially expressed (nominal P < 0.05). (E) Atrial Sgk1 mRNA expression in obese versus lean mice (left) and expression of phosphorylated (pSGK1), total SGK1 protein, and ratio as quantified by Western blotting (right). (F) Ventricular Sgk1 mRNA expression in obese versus lean mice (left) and expression of pSGK1, total SGK1 protein, and ratio as quantified by Western blotting (right). (G) Atrial expression of SGK1 phosphorylation targets NDRG1 and GSK3β in obese versus lean mice. The NDRG1 and GSK3β blots were from the same gel and so share a vinculin loading control. (H) Ventricular expression of SGK1 phosphorylation targets NDRG1 and GSK3β in obese versus lean mice. The NDRG1 and GSK3β blots were from the same gel and so share a vinculin loading control. For all parts of Figure 1, unpaired Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001. Number of mice in each group provided in the legend or bar graph or represented by the number of dots in individual figure.