Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity

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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Ranolazine may be the Best and Safest Pharmacologic Therapy For Congestive Heart Failure, And Safe, Effective For Ventricular And Atrial Arrhythmias

10.47890/ijpscp/garylmurray/2020/24148303 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Gary L Murray

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Sodium Channel ◽

Sodium Current ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Pharmacologic Therapy ◽

Ventricular Ejection Fraction ◽

Late Sodium Current ◽

Cardiac Sodium Channel

Background:Ranolazine (RAN) reduces cardiac sodium channel 1.5’s late sodium current(INaL ) in congestive heart failure (CHF), reducing myocardial calcium overload, potentially improving left ventricular ejection fraction(LVEF) and reducing arrhyth-mogenic after potentials. RAN blocks neuronal sodium channel 1.7(Nav 1.7), potentially altering parasympathetic and sympathetic (P&S) activity. RAN also selectively blocks inactivated atrial Nav 1.8, as well as ventricular IKr and ICaL ,affecting atrial and ventric-ular arrhythmias.

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Abstract 356: Loss of Function Mutations of Sodium Channel Beta-1 and Beta-2 Subunits Associated with Atrial Fibrillation and ST-segment Elevation

Circulation ◽

10.1161/circ.116.suppl_16.ii_54-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Hiroshi Watanabe ◽

Dawood Darbar ◽

Christiana R Ingram ◽

Kim Jiramongkolchai ◽

Sameer S Chopra ◽

...

Keyword(s):

Atrial Fibrillation ◽

Steady State ◽

Sodium Channel ◽

Sodium Current ◽

Β Subunit ◽

Loss Of Function ◽

St Segment Elevation ◽

Negative Shift ◽

St Segment ◽

Cardiac Sodium Channel

Background: We have recently reported mutations in the cardiac sodium channel gene SCN5A in 5.9% of patients with atrial fibrillation (AF). In this study, we tested the hypothesis that mutations in sodium channel β subunit genes SCN1B-4B contribute to AF susceptibility. Methods and results: All 4 βsubunit genes were resequenced in 376 patients with AF (118 patients with lone AF and 258 patients with AF and cardiovascular disease) and 188 ethnically-defined controls. We identified 2 non-synonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF; these occur at residues highly conserved across mammals and were absent in controls. In 3 of 4 mutation carriers, there was saddle back type ST-segment elevation in the right precordial leads of electrocardiogram. Transcripts encoding both SCN1B and SCN2B were detected in human atrium and ventricle. To assess function in vitro , CHO cells were transfected with SCN5A without β subunit, SCN5A with wild-type (WT) β subunit, or SCN5A with mutant β subunit: all 4 mutants altered SCN5A current to a variable extent compared to WT β subunits. WT β1 increased SCN5A currents by 75%, and induced a negative shift in steady-state activation (−10.2 mV) and inactivation (−6.7 mV), compared to SCN5A alone. D153N β1 caused partial loss of function, with increased SCN5A current but to a smaller extent (24%) than WT β1, and a negative shift in steady-state activation (−12.1 mV) and inactivation (−8.1 mV) similar to WT. R85H β1 produced a pure loss of function, with currents no different from SCN5A alone. WT β2 did not change SCN5A current amplitude, while R28Q β2 and R28W β2 decreased current by 36% and 30%, respectively; and positively shifted steady-state activation by +7.4 mV and +5.1 mV, respectively, compared to WT. Conclusion: Loss of function mutations in sodium channel β subunits were identified in patients with AF, and were associated with a distinctive ECG phenotype. These findings further support the hypothesis that decreased sodium current enhances AF susceptibility.

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Abstract 15925: Localization of Nav1.5 at the Intercellular Junctions Resolved by Diffraction-Unlimited Microscopy in Three Dimensions and by Correlative Light-Electron Microscopy

Circulation ◽

10.1161/circ.130.suppl_2.15925 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Alejandra Leo-Macias ◽

Esperanza Agullo-Pascual ◽

Eli Rothenberg ◽

Mario Delmar

Keyword(s):

Electron Microscopy ◽

Sodium Channel ◽

Ventricular Myocytes ◽

Sodium Current ◽

Intercellular Junctions ◽

Three Dimensions ◽

Macromolecular Complex ◽

Adult Heart ◽

Mechanical Coupling ◽

Cardiac Sodium Channel

Sodium current amplitude, kinetics and regulation depend on the properties of the pore-forming protein (mostly NaV1.5 in adult heart) and on the specific molecular partners with which the channel protein associates. The composition of the voltage-gated sodium channel macromolecular complex is location-specific; yet, the exact position of NaV1.5 in the subcellular landscape of the intercalated disc (ID), remains unclear. We implemented diffraction unlimited microscopy (direct stochastic optical reconstruction microscopy, or “dSTORM”) to localize the pore-forming subunit of the cardiac sodium channel NaV1.5 with a resolution of 20nm on the XY plane. In isolated adult ventricular myocytes, NaV1.5 was found in distinct semi-circular clusters. When the entire population of clusters within a 500 nm window from the ID was considered (more than 350 individual clusters analyzed), 75% of them localized to N-cadherin rich sites. NaV1.5-distal clusters were found at an average 313±15 nm from the cell end. Introducing an astigmatic lens in the light path allowed us to solve cluster location in three dimensions, at resolutions of 20 nm in XY and 40 nm in the z plane. Three-dimensional images confirmed the preferential localization at or near N-cadherin plaques, and further suggested that NaV1.5 arrives to the membrane via N-cadherin-anchored paths, most likely microtubules. In additional experiments, we developed a novel approach to correlate the image of NaV1.5 clusters by dSTORM with the cellular ultrastructure as resolved by electron microscopy on the same sample. This “correlative light-electron microscopy” method confirmed the preference of NaV1.5 clusters at sites of mechanical coupling. Overall, we provide the first ultrastructural description of NaV1.5 at the cardiac ID and its relation with the major electron-dense domains of the adult heart. Our data support a model by which microtubule-mediated delivery of NaV1.5 anchors at N-cadherin-rich sites, likely “mixed junctions” also containing desmosomal molecules (such as plakophilin-2; see Cerrone et al; Circulation 129:1092-1103, 2014) and connexin43. These findings have major implications to the understanding of sodium current disruption in diseases affecting the integrity of the ID.

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Faculty Opinions recommendation of Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1105193.561387 ◽

2008 ◽

Author(s):

Hugues Abriel

Keyword(s):

Atrial Fibrillation ◽

Sodium Channel ◽

Cardiac Sodium Channel

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Abstract 1503: Knockdown of Mog1 Expression Reduces Sodium Currents by Reducing the Trafficking of Cardiac Sodium Channel Na V 1.5 to the Cell Membrane

Circulation ◽

10.1161/circ.118.suppl_18.s_338-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Susmita Chakrabarti ◽

Sandro Yong ◽

Shin Yoo ◽

Ling Wu ◽

Qing Kenneth Wang

Keyword(s):

Sodium Channel ◽

Ventricular Myocytes ◽

Sodium Current ◽

Expression System ◽

Heart Association ◽

Hek293 Cells ◽

Similar Reduction ◽

Mammalian Expression ◽

Ventricular Cells ◽

Cardiac Sodium Channel

The cardiac sodium channel (Na v 1.5) plays a significant role in cardiac physiology and leads to cardiac arrhythmias and sudden death when mutated. Modulation of Na v 1.5 activity can also arise from changes to accessory subunits or proteins. Our laboratory has recently reported that MOG1, a small protein that is highly conserved from yeast to humans, is a co-factor of Na v 1.5. Increased MOG1 expression has been shown to increase Na v 1.5 current density. In adult mouse ventricular myocytes, these two proteins were found to be co-localized at the intercalated discs. Here, we further characterize the regulatory role of MOG1 using the RNA interference technique. Sodium current was recorded in voltage-clamp mode from a holding potential of −100 mV and activated to −20 mV. In 3-day old mouse neonatal ventricular cells transfected with siRNA against mouse MOG1 decreased sodium current densities (pA/pF) compared to control or scramble siRNA treated cells (−10.2±3.3, n=11 vs. −165±16, n=20 or −117.9±11.7, n=11). A similar reduction in sodium current was observed in mammalian expression system consisting of HEK293 cells stably expressing human Na v 1.5, by transfecting siRNAs against either human or mouse MOG1 (−41.7±8.3, n=7 or, −82.6±9.6, n=7 vs. −130.6±11.5, n=7; −111.5±8.5, n=7, respectively). Immunocytochemistry revealed that the expression of MOG1 and Na v 1.5 were decreased in both HEK and neonatal cells when compared to scramble siRNAs or control groups. These results show that MOG1 is an essential co-factor for Na v 1.5 by way of a channel trafficking. Such interactions between MOG1 and Na v 1.5 suggest that early localization of MOG1 on the membrane of neonatal cardiomyocytes may be necessary for proper localization and the distribution of Na v 1.5 during cardiac development. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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Late Sodium Current in Atrial Cardiomyocytes Contributes to the Induced and Spontaneous Atrial Fibrillation in Rabbit Hearts

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0000000000000883 ◽

2020 ◽

Vol 76 (4) ◽

pp. 437-444

Author(s):

Yanpeng Chu ◽

Qiaomei Yang ◽

Lu Ren ◽

Shandong Yu ◽

Zhipei Liu ◽

...

Keyword(s):

Atrial Fibrillation ◽

Sodium Current ◽

Late Sodium Current ◽

Atrial Cardiomyocytes

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Eleutheroside B, a selective late sodium current inhibitor, suppresses atrial fibrillation induced by sea anemone toxin II in rabbit hearts

Acta Pharmacologica Sinica ◽

10.1038/s41401-020-0453-z ◽

2020 ◽

Cited By ~ 1

Author(s):

Pei-pei Zhang ◽

Zhao-fu Guo ◽

Pei-hua Zhang ◽

Zhi-pei Liu ◽

Lv Song ◽

...

Keyword(s):

Atrial Fibrillation ◽

Sodium Current ◽

Sea Anemone ◽

Late Sodium Current ◽

Eleutheroside B ◽

Sea Anemone Toxin

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Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.120.008296 ◽

2020 ◽

Vol 13 (8) ◽

Cited By ~ 1

Author(s):

Mark D. McCauley ◽

Liang Hong ◽

Arvind Sridhar ◽

Ambili Menon ◽

Srikanth Perike ◽

...

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Ion Channel ◽

Sodium Channel ◽

Action Potential Duration ◽

Obese Mice ◽

Atrial Fibrosis ◽

Structural Remodeling ◽

Cardiac Sodium Channel ◽

Channel Expression

Background: Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing I Na , and enhancing susceptibility to AF. Methods: To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F 2 -isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes. Results: Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls ( P <0.01) with increased AF burden. Cardiac sodium channel expression, I Na and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current ( I Kur ) and F 2 -isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored I Na , I Ca,L , I Kur , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls. Conclusions: Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.

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