Suppression of hERG K+ current and cardiac action potential prolongation by 4-hydroxynonenal via dual mechanisms

• Published in: Redox biology 2018-10, Vol.19, p.190-199
• Main Authors: Choi, Seong Woo, Choi, Si Won, Jeon, Young Keul, Moon, Sung-Hwan, Zhang, Yin-Hua, Kim, Sung Joon
• Format: Article
• Language: English
• Subjects: 4-hydroxynonenal; Action Potentials; Aldehydes - metabolism; Animals; Cardiac action potential prolongation; Down-Regulation; Ether-A-Go-Go Potassium Channels - chemistry; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - metabolism; Guinea Pigs; HEK293 Cells; hERG channel; Humans; Lipid peroxidant; Lipid Peroxidation; Male; Oxidative Stress; Patch-Clamp Techniques; Protein Processing, Post-Translational; Research Paper
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2018.08.018

Oxidative stress under pathological conditions, such as ischemia/reperfusion and inflammation, results in the production of various reactive chemicals. Of these chemicals, 4-hydroxynonenal (4-HNE), a peroxidation product of ω6-polyunsaturated fatty acid, has garnered significant attention. However, the effect of 4-HNE on cardiac electrophysiology has not yet been reported. In the present study, we investigated the effects of 4-HNE on several cardiac ion channels, including human ether-a-go-go-related (hERG) channels, using the whole-cell patch clamp technique. Short-term exposure to 100 μM 4-HNE (4-HNE100S), which mimics local levels under oxidative stress, decreased the amplitudes of rapidly activating delayed rectifier K+ current (IKr) in guinea pig ventricular myocytes (GPVMs) and HEK293T cells overexpressing hERG (IhERG). MS analysis revealed the formation of 4-HNE-hERG adduct on specific amino acid residues, including C276, K595, H70, and H687. Long-term treatment (1–3 h) with 10 μM 4-HNE (4-HNE10L), suppressed IKr and IhERG, but not IKs and ICa,L. Action potential duration (APD) of GPVMs was prolonged by 37% and 64% by 4-HNE100S and 4-HNE10L, respectively. Western blot analysis using surface biotinylation revealed a reduction in mature membrane hERG protein after treatment with 4-HNE10L. Proteasomal degradation inhibitors, such as bortezomib, prevented the 4-HNE10L-induced decrease in mature hERG, suggesting a retrograde degradation of membrane hERG due to 4-HNE. Taken together, 4-HNE100S and 4-HNE10L suppressed IhERG via functional inhibition and downregulation of membrane expression of hERG, respectively. The exposure of 4-HNE under pathological oxidative stress may increase the risk of proarrhythmic events via APD prolongation. [Display omitted] •4-HNE-mediated hERG channel modification causes cardiac action potential prolongation.•4-HNE inhibits hERG channel by post-translational modification at Cys276, Lys595, His70, and His687.•Long-term exposure to 4-HNE decreases membrane hERG channel expression.