The rescuable function and mechanism of resveratrol on As2O3-induced hERG K+ channel deficiency

Abstract

Arsenic trioxide (As2O3) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As2O3-insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As2O3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As2O3-caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As2O3 on cardiotoxicity.

Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency

“…We first chose the cardioprotective drug, resveratrol, which was used to correct trafficking defect caused by arsenic trioxide via acceleration of interaction between hERG and chaperones, and alleviation of ER stress. 14 In addition, resveratrol shortened APD 50 and APD 90 recorded in freshly isolated guinea pig ventricular myocytes by inhibition of I ca-L and restoration of I kr when co-incubated with arsenic trioxide. We also used astemizole (an antihistamine drug), a high-affinity blocker of hERG channel, which is thought to interact with the amino acid residue Tyr652.…”

“…Resveratrol is able to rescue the trafficking inhibition of hERG and relieve the ER stress triggered by arsenic trioxide. 14 Astemizole promotes forward trafficking from ER to cell surface inhibited by pentamidine in a competitive way. 5 Fexofenadine is often used to rescue trafficking defect of hERG because of the advantage that rescue without blocking the channel.…”

“…The procedure of myocyte isolation was done as described previously. 14 Briefly, the guinea pigs were killed by cervical dislocation and their hearts were rapidly retrogradely perfused on a modified Langendorff perfusion apparatus with Tyrode’s solution (136 mM NaCl, 5.4 mM KCl, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 0.33 mM NaH 2 PO 4 , 10 mM glucose, and 10 mM HEPES, with pH 7.4) at 37°C for a few minutes until the effluent is without blood. Then, the heart was perfused with Ca 2+ -free Tyrode’s solution till the heart stopped beating, followed by the perfusion in the same solution containing 150 kU⋅L −1 type II collagenase (Worthington Biochemical Corporation, Lakewood, New Jersey, USA) and 1% bovine serum albumin (Huashun Biotechnology, Wuhan, Hubei Province, People’s Republic of China).…”

Mechanisms underlying probucol-induced hERG-channel deficiency

“…These findings indicated that As 2 O 3 -induced hERG-channel abnormality was probably due to other reasons, like trafficking deficiency. 10 …”

“… 8 Also, probucol and As 2 O 3 are the two main kinds of drugs to decrease hERG expression and subsequently cause LQTS. 9 , 10 Therefore, we wondered whether these two drugs, which can induce hERG-channel deficiency, were involved in the ubiquitination protein-degradation pathway. Based on this, we became interested in SGK1 expression after treatment with different concentrations of probucol or As 2 O 3 in hERG-HEK293 cells.…”