摘要：SummaryCardiovascular diseases remain the leading cause of death worldwide. Most deaths are sudden and occur secondary to the occlusion of coronary arteries resulting in a rapid decrease in cellular oxygen levels. Acute hypoxia is proarrhythmic, leading to disordered electrical signals, conduction block, and uncoordinated beating of the myocardium. Although acute hypoxia is recognized to perturb the electrophysiology of heart muscle, the mechanistic basis for the effect has remained elusive, hampering the development of targeted therapeutic interventions. Here, we show that acute hypoxia activates the redox-sensitive SUMO pathway in cardiomyocytes, causing rapid inhibition of the inward-rectifying K+channel, Kir2.1. We find that SUMOylation decreases the activation of Kir2.1 channels by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). These data provide a mechanistic basis for the proarrhythmic effects of acute hypoxia and offer a framework for understanding the central role of PIP2in mediating the sequelae of hypoxia and SUMOylation in cardiovascular disease.Graphical abstractDisplay OmittedHighlights•Acute hypoxia inhibits the inward rectifying K+current,IK1in cardiomyocytes•Hypoxic inhibition ofIK1results from rapid SUMOylation of Kir2.1 channels•SUMOylation decreases the potency and efficacy of PIP2to activate Kir2.1 channels•An exogenous PIP2analog opposes hypoxic inhibition ofIK1and Kir2.1 channelsBiological sciences; Molecular biology; Cell biology
