Key result
In vivo administration of a synthetic PY peptide to suppress Nedd4-2 shortened the prolonged QTc interval, enhanced IKr, and reduced the incidence of sudden death from 42.9% to 20% in guinea pigs with pathological cardiac hypertrophy.
Why the study?
Reduction of I Kr in pathological cardiac hypertrophy contributes to arrhythmia susceptibility, but practical approaches to prevent I Kr deficiency are lacking.
Does pharmacological suppression of Nedd4-2 prevent IKr deficiency and reduce arrhythmia susceptibility in pathological cardiac hypertrophy?
Does pharmacological suppression of Nedd4-2 prevent IKr deficiency and reduce arrhythmia susceptibility in pathological cardiac hypertrophy?
Absolute Event Rate: 20% vs 42.9%
Pharmacological suppression of Nedd4-2-dependent ubiquitination prevents IKr deficiency and represents a potential novel antiarrhythmic approach in pathological cardiac hypertrophy.
May restore IKr and curb arrhythmias in hypertrophy models; leaves open human translation.
The human ether-á-go-go-related gene (hERG) encodes the pore-forming subunit (Kv11.1), conducting a rapidly delayed rectifier K + current ( I Kr ). Reduction of I Kr in pathological cardiac hypertrophy (pCH) contributes to increased susceptibility to arrhythmias. However, practical approaches to prevent I Kr deficiency are lacking. Our study investigated the involvement of ubiquitin ligase Nedd4-2-dependent ubiquitination in I Kr 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 I Kr 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 I Kr 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, in vivo administration of the PY peptide shortened QT interval and action potential duration, and enhanced I Kr in pCH. We conclude that Nedd4-2-dependent ubiquitination is critically involved in I Kr deficiency in pCH. Pharmacological suppression of Nedd4-2 represents a novel approach for antiarrhythmic therapy in pCH.
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Zhang et al. (2022) studied Pathological cardiac hypertrophy. Synthetic PY peptide (Nedd4-2 suppression) vs. Angiotensin II alone (Vehicle) was evaluated on Incidence of sudden death. In vivo administration of a synthetic PY peptide to suppress Nedd4-2 shortened the prolonged QTc interval, enhanced IKr, and reduced the incidence of sudden death from 42.9% to 20% in guinea pigs with pathological cardiac hypertrophy.
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