AUTHOR=Zhang Hua , Fu Tian , Sun Jinglei , Zou Sihao , Qiu Suhua , Zhang Jiali , Su Shi , Shi Chenxia , Li De-Pei , Xu Yanfang 

TITLE=Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.942769

DOI=10.3389/fphar.2022.942769

ISSN=1663-9812

ABSTRACT=<p>The human <italic>ether-á-go-go-related</italic> gene (hERG) encodes the pore-forming subunit (Kv11.1), conducting a rapidly delayed rectifier K<sup>+</sup> current (<italic>I</italic><sub>Kr</sub>). Reduction of <italic>I</italic><sub>Kr</sub> in pathological cardiac hypertrophy (pCH) contributes to increased susceptibility to arrhythmias. However, practical approaches to prevent <italic>I</italic><sub>Kr</sub> deficiency are lacking. Our study investigated the involvement of ubiquitin ligase Nedd4-2-dependent ubiquitination in <italic>I</italic><sub>Kr</sub> reduction and sought an intervening approach in pCH. Angiotensin II (Ang II) induced a pCH phenotype in guinea pig, accompanied by increased incidences of sudden death and higher susceptibility to arrhythmias. Patch-clamp recordings revealed a significant <italic>I</italic><sub>Kr</sub> reduction in pCH cardiomyocytes. Kv11.1 protein expression was decreased whereas its mRNA level did not change. In addition, Nedd4-2 protein expression was increased in pCH, accompanied by an enhanced Nedd4-2 and Kv11.1 binding detected by immunoprecipitation analysis. Cardiac-specific overexpression of inactive form of Nedd4-2 shortened the prolonged QT interval, reversed <italic>I</italic><sub>Kr</sub> reduction, and decreased susceptibility to arrhythmias. A synthesized peptide containing the PY motif in Kv11.1 C-terminus binding to Nedd4-2 and a cell-penetrating sequence antagonized Nedd4-2-dependent degradation of the channel and increased the surface abundance and function of hERG channel in HEK cells. In addition, <italic>in vivo</italic> administration of the PY peptide shortened QT interval and action potential duration, and enhanced <italic>I</italic><sub>Kr</sub> in pCH. We conclude that Nedd4-2-dependent ubiquitination is critically involved in <italic>I</italic><sub>Kr</sub> deficiency in pCH. Pharmacological suppression of Nedd4-2 represents a novel approach for antiarrhythmic therapy in pCH.</p>