Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Wan, Elaine; Abrams, Jeffrey S.; Weinberg, Richard L.; Katchman, Alexander N.; Bayne, Joseph; Zakharov, Sergey I.; Yang, Lin; Morrow, John; Garan, Hasan; Marx, Steven O.

doi:10.1172/jci84669

Cited by 71 publications

(82 citation statements)

References 53 publications

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“…While we cannot definitively rule out involvement of cytoskeletal components, we see no evidence to support a mechanism that involves disruption of proteins interacting with voltage-gated ion channel alpha subunits, as no change in current densities of any cardiomyocyte voltage-gated ionic current was observed [18, 19]. Thus, aberrant Ca 2+ homeostasis secondary to aberrant electrical signaling remains a potential mechanism; calcineurin activity might be affected by a sustained change in cytosolic Ca 2+ levels through one of many possible mechanisms as described by others [5, 13, 26, 46, 48, 63]; future studies will investigate the viability of such a mechanism.…”

Section: Discussionmentioning

confidence: 99%

Aberrant sialylation causes dilated cardiomyopathy and stress-induced heart failure

Deng

Ednie

et al. 2016

Basic Res Cardiol

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Dilated cardiomyopathy (DCM), the third most common cause of heart failure, is often associated with arrhythmias and sudden cardiac death if not controlled. The majority of DCM is of unknown etiology. Protein sialylation is altered in human DCM, with responsible mechanisms not yet described. Here we sought to investigate the impact of clinically relevant changes in sialylation on cardiac function using a novel model for altered glycoprotein sialylation that leads to DCM and to chronic stress-induced heart failure (HF), deletion of the sialyltransferase, ST3Gal4. We previously reported that 12- to 20-week-old ST3Gal4−/− mice showed aberrant cardiac voltage-gated ion channel sialylation and gating that contribute to a pro-arrhythmogenic phenotype. Here, echocardiography supported by histology revealed modest dilated and thinner-walled left ventricles without increased fibrosis in ST3Gal4−/− mice starting at 1 year of age. Cardiac calcineurin expression in younger (16–20 weeks old) ST3Gal4−/− hearts was significantly reduced compared to WT. Transverse aortic constriction (TAC) was used as a chronic stressor on the younger mice to determine whether the ability to compensate against a pathologic insult is compromised in the ST3Gal4−/− heart, as suggested by previous reports describing the functional implications of reduced cardiac calcineurin levels. TAC’d ST3Gal4−/− mice presented with significantly reduced systolic function and ventricular dilation that deteriorated into congestive HF within 6 weeks post-surgery, while constricted WT hearts remained well-adapted throughout (ejection fraction, ST3Gal4−/− = 34 ± 5.2 %; WT = 53.8 ± 7.4 %; p < 0.05). Thus, a novel, sialo-dependent model for DCM/HF is described in which clinically relevant reduced sialylation results in increased arrhythmogenicity and reduced cardiac calcineurin levels that precede cardiomyopathy and TAC-induced HF, suggesting a causal link among aberrant sialylation, chronic arrhythmia, reduced calcineurin levels, DCM in the absence of a pathologic stimulus, and stress-induced HF.

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Section: Discussionmentioning

confidence: 99%

Aberrant sialylation causes dilated cardiomyopathy and stress-induced heart failure

Deng

Ednie

et al. 2016

Basic Res Cardiol

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“…Telmisartan is commonly used with Ran in patients with microvascular angina pectoris . Therefore, besides the blockade of AT 1 receptor, the stimulatory effects of TEL on I Na at concentrations used in this study may occur within the therapeutic range, and they could be a potentially important mechanism through which the drug perturbs membrane excitability (eg, diminished post‐repolarization refractoriness) of heart cells occurring in vivo . Indeed, the TEL‐induced shortening of the atrial electromechanical delay reported previously may be ascribed partly to the ability of the drug to stimulate I Na in atrial cells, as shown here.…”

Section: Discussionmentioning

confidence: 74%

Activation of voltage‐gated sodium current and inhibition of erg‐mediated potassium current caused by telmisartan, an antagonist of angiotensin II type‐1 receptor, in HL‐1 atrial cardiomyocytes

Chang

2018

Clin Exp Pharma Physio

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Telmisartan (TEL) is a non-peptide blocker of angiotensin II type-1 (AT ) receptor. However, the mechanisms through which this drug interacts directly with ion currents in hearts remain largely unclear. Herein, we aim to investigate the effects of TEL the on ionic currents and membrane potential of murine HL-1 cardiomyocytes. In whole-cell recordings, addition of TEL stimulated the peak and late components of voltage-gated Na currents (I ) with different potencies. The EC values required to achieve the stimulatory effect of this drug on peak and late I were 0.2 and 1.2 μmol/L, respectively, and the current-voltage relationship of peak I shifted toward less-depolarized potentials during exposure to TEL. Telmisartan not only increased peak I but also prolonged the inactivation time course of late I . Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL-mediated effects. The drug enhanced the recovery rate of I inactivation and exerted an inhibitory effect on erg-mediated K and L-type Ca currents. In whole-cell current-clamp recordings, addition of the drug resulted in prolongation of the duration of action potentials (APs) in a dose-dependent manner in HL-1 cells; Amio or Ran could reverse this increase in AP durations. Telmisartan-mediated prolongation of AP was attenuated in KCNH2 siRNA-transfected HL-1 cells. In cultured smooth muscle cells of the human coronary artery, TEL enhanced I amplitudes and slowed current inactivation. Stimulation by TEL of I in HL-1 cells did not simply increase current magnitude but altered current kinetics, thereby suggesting state-dependent activation. Telmisartan may have greater affinity to the open/inactivated state than to the resting state residing in Na channels. Collectively, TEL-mediated stimulation of I and inhibition of I could be an important ionic mechanism underlying the increased cell excitability of HL-1 cells; these actions, however, cannot be entirely explained by its blockade of AT receptor.

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“…However, a tremendous amount of knowledge indicates that the alteration of sodium current (I Na ) activity can directly impair cardiac structure and function independently of effects of arrhythmia, suggesting that DCM may be the directed result of SCN5A genetic variants [20][21][22]. A study on transgenic mice without any arrhythmias displayed that the level of the reduction in Na + current was closely related to the severity of DCM [16].…”

Section: Discussionmentioning

confidence: 99%

Effects of SCN5A mutation on intracellular calcium concentration

Gao

Shi²,

Ma³

et al. 2017

JBT

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Abstract:Objective: To construct the delQKP1507-1509 mutant of SCN5A channel, and observe the effects of this mutation on intracellular calcium concentration. Methods: SCN5A delQKP1507-1509 mutation was engineered using site-directed mutagenesis. Wild-type (WT), mutant (MT) and mixed (the mixture of wild-type and mutant plasmids at a ratio of 1:1) Nav1.5 plasmids were transfected into human embryonic kidney 293 (HEK293) mimicking the heterozygous state were 79.3683±3.051, 94.6165±8.383, 90.7463±6.421 respectively, and there was no significant difference among these three groups (P>0.05). Conclusions: SCN5A delQKP1507-1509 mutant is successfully constructed and transfected into HEK293 cells. The mutation does not affect calcium concentration and further study is required to describe the possible pathophysiological mechanisms of dilated cardiomyopathy phenotype in sodium channel overlap syndromes caused by this SCN5A delQKP1507-1509 mutation.

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Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Cited by 71 publications

References 53 publications

Aberrant sialylation causes dilated cardiomyopathy and stress-induced heart failure

Aberrant sialylation causes dilated cardiomyopathy and stress-induced heart failure

Activation of voltage‐gated sodium current and inhibition of erg‐mediated potassium current caused by telmisartan, an antagonist of angiotensin II type‐1 receptor, in HL‐1 atrial cardiomyocytes

Effects of SCN5A mutation on intracellular calcium concentration

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