Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity
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Date
2021-04
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Abstract
Background: Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing
evidence identifying obesity as an important risk factor for the development of AF. Although
defective atrial myocyte excitability due to stress-induced remodeling of ion channels is
commonly observed in the setting of AF, little is known about the mechanistic link between
obesity and AF. Recent studies have identified increased cardiac late sodium current (INa,L)
downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of
AF susceptibility.
Methods: Here, we investigated a possible role for CaMKII-dependent INa,L in obesity-induced
AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the
Nav1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice).
Results: A high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA
mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis
and decreased body weight compared to WT mice. However, SA mice also had reduced food
consumption compared to WT mice. Controlling for food consumption through pair feeding of
WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial
fibrosis, premature atrial contractions or metabolic capacity.
Conclusions: These data demonstrate a novel role for CaMKII-dependent regulation of Nav1.5 in
mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet induced obesity.
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Poster Division: Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
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Published version: Dewal RS, Greer-Short A, Lane C, Nirengi S, Manzano PA, Hernández-Saavedra D, Wright KR, Nassal D, Baer LA, Mohler PJ, Hund TJ, Stanford KI. Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity. Int J Obes (Lond). 2021 Apr;45(4):795-807. doi: 10.1038/s41366-021-00742-4. Epub 2021 Jan 26. PMID: 33500550; PMCID: PMC8005377.