Aconitine Induces TRPV2-Mediated Ca2+ Influx through the p38 MAPK Signal and Promotes Cardiomyocyte Apoptosis.

Xiaoyan Zeng,Junbo Zhu,Zhongfeng Cheng,Yangshan Fu,Feng Zhang,Chunai Yang

doi:10.1155/2021/9567056

Abstract

Aconitine is the main effective component of traditional Chinese medicine Aconitum, which has been proved to have severe cardiovascular toxicity. The toxic effect of aconitine on cardiomyocytes is related to intracellular calcium overload, but the mechanism remains unclear. The aim of this study was to explore the mechanism of aconitine inducing intracellular Ca2+ overload and promoting H9c2 cardiomyocyte apoptosis through transient receptor potential cation channel subfamily V member 2 (TRPV2). After treated with different concentrations of aconitine, the level of cell apoptosis, intracellular Ca2+, and expression of p-p38 MAPK and TRPV2 of H9c2 cardiomyocytes were detected. The results showed that aconitine induced Ca2+ influx and H9c2 cardiomyocyte apoptosis in a dose-dependent manner and promoted p38 MAPK activation as well as TRPV2 expression and plasma membrane (PM) metastasis. siTRPV2, tranilast, and SB202190 reversed intracellular Ca2+ overload and H9c2 cardiomyocyte apoptosis induced by aconitine. These results suggested that aconitine promoted TRPV2 expression and PM metastasis through p38 MAPK signaling, thus inducing intracellular Ca2+ overload and cardiomyocyte apoptosis. Furthermore, TRPV2 is a potential molecular target for the treatment of aconitine poisoning.

Highlights

Aconitum species, containing aconitine, are widely used in the clinical treatment of rheumatism, arthritis, bruise, fracture, pain, and other diseases in Control of Pharmaceutical and Biological Products (China) and other Asian countries because of their medicinal properties
Aconitine induced obvious H9c2 cell apoptosis at a lower dose of 0.25 μM, and the effect of aconitine on H9c2 cardiomyocyte apoptosis was dose dependent (Figures 1(a) and 1(b)). e levels of apoptosis-related proteins were carried out by western blotting (Figure 1(c)); the results showed that the expression of antiapoptotic protein Bcl-2 in H9c2 cells was reduced by aconitine at a dose-dependent manner, while the expressions of proapoptotic proteins Bax and cleaved caspase-3 were upregulated by aconitine at a dose-dependent manner (Figure 1(d))
Aconitine obviously induced a Ca2+ influx which led to a significant intracellular Ca2+ overload of H9c2 cardiomyocytes in a dose-dependent manner (Figure 1(e)). ese results indicated that aconitine could promote apoptosis by inducing intracellular Ca2+ overload

Summary

Introduction

Aconitum species, containing aconitine, are widely used in the clinical treatment of rheumatism, arthritis, bruise, fracture, pain, and other diseases in China and other Asian countries because of their medicinal properties. Due to their potential proarrhythmic effect, Aconitum and its related preparations are restrictively used in the treatment of rheumatoid arthritis and some cardiovascular diseases [1]. As the main toxic ingredient and effective agent of Aconitum, aconitine is a natural diterpene alkaloid [2], which was reported to be an inducer of lethal ventricular arrhythmias through rapidly inhibiting or activating different ion channels on cardiac myocytes or conductive cells [3]. The cytotoxic signaling pathway of aconitine-induced cardiomyocyte injury remains to be further studied

Methods

Results

Conclusion