Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure

Carmen A Ufret-Vincenty,Deborah J Baro,W Jonathan Lederer,Howard A Rockman,Luis E Quiñones,L Fernando Santana

doi:10.1074/jbc.m102548200

Abstract

We investigated the cellular and molecular mechanisms underlying arrhythmias in heart failure. A genetically engineered mouse lacking the expression of the muscle LIM protein (MLP-/-) was used in this study as a model of heart failure. We used electrocardiography and patch clamp techniques to examine the electrophysiological properties of MLP-/- hearts. We found that MLP-/- myocytes had smaller Na+ currents with altered voltage dependencies of activation and inactivation and slower rates of inactivation than control myocytes. These changes in Na+ currents contributed to longer action potentials and to a higher probability of early afterdepolarizations in MLP-/- than in control myocytes. Western blot analysis suggested that the smaller Na+ current in MLP-/- myocytes resulted from a reduction in Na+ channel protein. Interestingly, the blots also revealed that the alpha-subunit of the Na+ channel from the MLP-/- heart had a lower average molecular weight than in the control heart. Treating control myocytes with the sialidase neuraminidase mimicked the changes in voltage dependence and rate of inactivation of Na+ currents observed in MLP-/- myocytes. Neuraminidase had no effect on MLP-/- cells thus suggesting that Na+ channels in these cells were sialic acid-deficient. We conclude that deficient glycosylation of Na+ channel contributes to Na+ current-dependent arrhythmogenesis in heart failure.

Highlights

Cardiac arrhythmias are a leading cause of death among patients with HF1 [1]
Action Potential Prolongation and Early Afterdepolarizations in MLPϪ/Ϫ Cells—We examined the electrical activity of ventricular myocytes with HF and contractile dysfunction using whole animal electrocardiograph (ECG) measurements and single cell APs
In this paper we have examined the electrical activity of hearts with contractile dysfunction

Summary

Introduction

Cardiac arrhythmias are a leading cause of death among patients with HF1 [1]. the cellular and molecular changes in cardiac myocytes with contractile dysfunction. The cellular and molecular processes that underlie AP prolongation have been attributed to the following: 1) altered Kϩ channel currents [3,4,5,6,7,8,9,10,11], 2) changes in Naϩ channel currents [12,13,14,15], and 3) altered Ca2ϩ signaling (16 –18). These alterations are often brought about by changes in the amount or identity of specific ion channels or Ca2ϩ-signaling proteins [11, 19, 20]. We conclude that incomplete glycosylation during post-translational processing contributes to Naϩ channel-dependent arrhythmogenesis in HF

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Conclusion