Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels

Abstract

Acute cardiac hypoxia produces life-threatening elevations in late sodium current (I_LATE) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of Na_V1.5 channels so they reopen when normally inactive, late in the action potential. Na_V1.5 is SUMOylated only on lysine 442, and the mutation of that residue, or application of a deSUMOylating enzyme, prevents hypoxic reopenings. The time course of SUMOylation of single channels in response to hypoxia coincides with the increase in I_LATE, a reaction that is complete in under 100 s. In human cardiac myocytes derived from pluripotent stem cells, hypoxia-induced I_LATE is confirmed to be SUMO-dependent and to produce action potential prolongation, the pro-arrhythmic change observed in patients.

Keywords: I(LATE); NaV1.5; SCN5A; SENP; SUMO; arrythmia; cardiomyocyte; hypoxia; late current; sudden death.