Genetic Inhibition of Serum Glucocorticoid Kinase 1 Prevents Obesity-related Atrial Fibrillation

Bapat, A.; Li, G.; Xiao, L.; Hulsmans, M.; Schloss, M. J.; Iwamoto, Y.; Tedeschi, J.; Yang, X.; Nahrendorf, M.; Rosenzweig, A.; Ellinor, P.; Das, S.; Milan, D.

doi:10.1101/2021.05.20.444790

bioRxiv · 10.1101/2021.05.20.444790

Genetic Inhibition of Serum Glucocorticoid Kinase 1 Prevents Obesity-related Atrial Fibrillation

Bapat, A.·Li, G.·Xiao, L.·Hulsmans, M.·Schloss, M. J.·Iwamoto, Y.·Tedeschi, J.·Yang, X.·Nahrendorf, M.·Rosenzweig, A.·Ellinor, P.·Das, S.·Milan, D.

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Abstract

RationaleGiven its rising prevalence in both the adult and pediatric populations, obesity has become an increasingly important risk factor in the development of atrial fibrillation. However, a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned downstream of multiple obesity-related pathways, and prior work has shown a pathologic role for SGK1 signaling in ventricular remodeling and arrhythmias. ObjectiveTo determine the mechanistic basis of obesity associated atrial fibrillation and explore the therapeutic potential of targeting SGK1 in this context. Methods and ResultsWe utilized a mouse model of diet induced obesity to determine the atrial electrophysiologic effects of obesity using electrophysiologic studies, optical mapping, and biochemical analyses. In C57BL/6J mice fed a high fat diet, there was upregulation of SGK1 signaling along with an increase in AF inducibility determined at electrophysiology (EP) study. These changes were associated with an increase in fibrotic and inflammatory signaling. Transgenic mice expressing a cardiac specific dominant negative SGK1 (SGK1 DN) were protected from obesity-related AF as well as the fibrotic and inflammatory consequences of AF. Finally, optical mapping demonstrated a shorter action potential duration and patch clamp revealed effects on INa, with a decreased peak current as well as a depolarizing shift in activation/inactivation properties in atrial myocytes. ConclusionsDiet induced obesity leads to increased cardiac SGK1 signaling as well as an increase in AF inducibility in obese mice. Genetic SGK1 inhibition reduced AF inducibility, and this effect may be mediated by effects on inflammation, fibrosis, and cellular electrophysiology.

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Bapat, A., Li, G., Xiao, L., Hulsmans, M., Schloss, M. J., Iwamoto, Y., Tedeschi, J., Yang, X., Nahrendorf, M., Rosenzweig, A., Ellinor, P., Das, S., Milan, D.. 2021-05-21. Genetic Inhibition of Serum Glucocorticoid Kinase 1 Prevents Obesity-related Atrial Fibrillation. https://doi.org/10.1101/2021.05.20.444790

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