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Probucol-induced hERG Channel Reduction can be Rescued by Matrine and Oxymatrine in vitro
Yuan-Qi Shi1, Pan Fan2, Guo-Cui Zhang3
1Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, China.
Current Pharmaceutical Design
|October 29, 2019
Summary
Matrine and oxymatrine rescue probucol-induced hERG channel deficiency by upregulating Sp1 expression. These findings suggest potential therapeutic strategies for Long QT Syndrome (LQTs).
Area of Science:
- Cardiovascular Pharmacology
- Molecular Cardiology
Background:
- The human ether-a-go-go-related gene (hERG) potassium channel is vital for cardiac repolarization.
- Reduced hERG current is linked to Long QT Syndrome (LQTs).
- Probucol inhibits hERG expression, inducing LQTs, with no current effective treatment.
Purpose of the Study:
- To investigate the potential of matrine and oxymatrine to counteract probucol-induced hERG channel deficiency.
- To elucidate the underlying molecular mechanisms of probucol-induced hERG inhibition and matrine/oxymatrine's rescue effects.
Main Methods:
- Patch-clamp electrophysiology to assess hERG current and action potential duration (APD).
- Western blot analysis to quantify protein expression levels.
- Primary neonatal cardiac myocyte culture.
Main Results:
- Matrine and oxymatrine (1 μM) restored probucol-impaired hERG current and surface expression.
- These compounds shortened probucol-induced APD prolongation in cardiac myocytes.
- A novel mechanism involving probucol-induced downregulation of Sp1 (hERG gene transactivator) was identified.
- Matrine and oxymatrine upregulated Sp1 expression, potentially rescuing hERG deficiency.
Conclusions:
- Matrine and oxymatrine demonstrate efficacy in rescuing probucol-induced hERG deficiency in vitro.
- These findings offer a promising therapeutic avenue for acquired LQT2 caused by probucol.
