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Mechanism of hERG current inhibition by 4‐hydroxynonenal (4‐HNE), a polyunsaturated fatty acid‐derived electrophile
Author(s) -
Kim Sung Joon,
Choi Seong Woo,
Jang Ji Hyun,
Lee HyangAe,
Zhang Yin Hua Hua
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1007.26
Subject(s) - herg , chemistry , 4 hydroxynonenal , pharmacology , lysosome , biochemistry , lipid peroxidation , oxidative stress , endocrinology , biology , enzyme , potassium channel
Under oxidative stress, peroxidation of ω6‐polyunsaturated fatty acids produces 4‐Hydroxynonenal (4‐HNE), a highly reactive electrophile forming 4‐HNE‐protein adducts. Here we investigate the effects of 4‐HNE on cardiac hERG current that is a major target of arrhythmogenic conditions. Acute application of 4‐HNE (30~100 μM) decreased the tail current of hERG (I hERG,tail ), that was reversed by TCEP, a membrane impermeable reducing agent. The action potential duration (APD) of guinea‐pig ventricular myocytes (GPVMs) was prolonged by 4‐HNE. Chronic incubation (1–3 h) with lower concentration of 4‐HNE (10 μM) induced time‐dependent suppression of I hERG,tail and prolongation of APD in GPCMs, that was not reversed by TCEP treatment. Western blot analysis revealed that mature glycosylated hERG (155 kDa) is reduced by the chronic 4‐HNE (10 μM, 1–12 h). In total cell preparations, the decrease of mature hERG was partly rescued by proteasome‐ and lysosome‐dependent degradation inhibitors, bortezomib and bafilomycin, respectively. However, reduction of hERG proteins in the plasma membrane fraction and the inhibition of I hERG,tail by the chronic 4‐HNE treatment were not prevented by bortezomib and bafilomycin. Taken together, it is suggested that the electrophilic binding of 4‐HNE with extracellular domain acutely inhibits hERG activity. Also, the sustained exposure to 4‐HNE may accelerate the degradation of hERG proteins through proteasome‐ and lysosome‐dependent process. The suppression of hERG by 4‐HNE may participate in proarrhythmic effects of endogenous lipid peroxidants under pathological conditions.