Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity
| Autor: | Cemantha Lane, Revati S. Dewal, Shinsuke Nirengi, Pedro Acosta Manzano, Drew M. Nassal, Peter J. Mohler, Amara Greer-Short, Kristin I. Stanford, Katherine R. Wright, Diego Hernández-Saavedra, Thomas J. Hund, Lisa A. Baer |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Nutrition and Dietetics biology Kinase business.industry Premature atrial contraction Endocrinology Diabetes and Metabolism Sodium channel Medicine (miscellaneous) Atrial fibrillation Metabolism 030204 cardiovascular system & hematology Nav1.5 medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology Internal medicine Ca2+/calmodulin-dependent protein kinase medicine biology.protein Glucose homeostasis business |
| Zdroj: | International Journal of Obesity. 45:795-807 |
| ISSN: | 1476-5497 0307-0565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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