Deficient glycosylation of sodium channels in MLP-/- mice contributed to smaller Na+ currents, longer action potentials, and a higher probability of early afterdepolarizations in heart failure.
Deficient sialic acid glycosylation of sodium channels in heart failure alters sodium currents and promotes arrhythmogenesis.
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.
Ufret-Vincenty et al. (Sun,) conducted a other in Heart failure and cardiac arrhythmias. MLP-/- genetic knockout / Neuraminidase vs. Control myocytes was evaluated on Electrophysiological properties of myocytes (Na+ currents, action potentials, early afterdepolarizations). Deficient glycosylation of sodium channels in MLP-/- mice contributed to smaller Na+ currents, longer action potentials, and a higher probability of early afterdepolarizations in heart failure.