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

Acute cardiac hypoxia produces life-threatening elevations in late sodium current (ILATE) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of NaV1.5 channels so they reopen when normally inactive, late in the action potential. NaV1.5 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 ILATE, a reaction that is complete in under 100 s. In human cardiac myocytes derived from pluripotent stem cells, hypoxia-induced ILATE is confirmed to be SUMO-dependent and to produce action potential prolongation, the pro-arrhythmic change observed in patients. [Display omitted] •Acute cardiac hypoxia elevates late sodium current (ILATE) to pro-arrhythmic levels•Increased ILATE is due to rapid SUMOylation of NaV1.5 channels at the cell membrane•SUMOylation of lysine442 reopens NaV1.5 channels when they are normally inactive•Blocking SUMOylation prevents increased ILATE and action potential prolongation The cardiac channel NaV1.5 passes pro-arrhythmic late sodium currents in response to hypoxia. Plant et al. demonstrate the pathophysiological mechanism to be rapid, hypoxia-induced monoSUMOylation of NaV1.5 channels. Blocking SUMOylation of lysine442 prevents hypoxia-induced late currents and attendant prolongation of the action potential in human cardiomyocytes derived from pluripotent stem cells.