Hypoxia inhibits the cardiac IK1 current through SUMO targeting Kir2.1 activation by PIP2
Yu Xu,
Yuchen Yang,
Aishwarya Chandrashekar,
Kirin D. Gada,
Meghan Masotti,
Austin M. Baggetta,
Jenna G. Connolly,
Takeharu Kawano,
Leigh D. Plant
Affiliations
Yu Xu
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Yuchen Yang
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Aishwarya Chandrashekar
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Kirin D. Gada
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Meghan Masotti
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Austin M. Baggetta
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Jenna G. Connolly
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Takeharu Kawano
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA
Leigh D. Plant
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA; Center for Drug Discovery, Northeastern University, Boston, MA, USA; Corresponding author
Summary: Cardiovascular 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 PIP2 in mediating the sequelae of hypoxia and SUMOylation in cardiovascular disease.
