Notch1-Mediated Histone Demethylation of HCN4 Contributes to Aconitine-induced Ventricular Myocardial Dysrhythmia.

Notch1-Mediated Histone Demethylation of HCN4 Contributes to Aconitine-induced Ventricular Myocardial Dysrhythmia. Toxicol Lett. 2020 Mar 28;: Authors: Zhou W, Qiu LZ, Liu H, Deng HF, Yue LX, Gao Y Abstract Traditional Chinese Medicines (TCMs)-containing aconitine are popular and indispensable home remedies in Asia for thousands of years due to its excellent pharmaceutical effects. Accumulating evidence has identified that repeated-dose of aconitine could cause polymorphic ventricular arrhythmias. However, underlying molecular mechanisms are still not fully understood. Hence, the present study firstly investigated the potential role of Notch1 signaling in aconitine-induced cardiotoxicity, aiming to elaborate possible molecular mechanisms involved in aconitine triggered ventricular arrhythmias. Our results showed that aconitine increased Notch1 signaling and downstream KDM5A expression in human and rat cardiomyocytes at non-detectable cytotoxic doses. Furthermore, aconitine promoted the formation of a new regulatory complex containing NICD and KDM5A in a CK2αHI regime, which then targeted to HCN4 promoter and induced re-expression of HCN4 in mature cardiomyocytes. Ultimately, HCN4-mediated If current contributed to aconitine-caused alterations in beating rate of rat cardiomyocytes. All changes aforementioned were significantly ameliorated by Notch1 inhibitor, suggesting that Notch1-mediated epigenetic regulation of HCN4 contributes t...
Source: Toxicology Letters - Category: Toxicology Authors: Tags: Toxicol Lett Source Type: research