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

Yang, Chunai; Zeng, Xiaoyan; Cheng, Zhongfeng; Zhu, Junbo; Fu, Yangshan

doi:10.1155/2021/9567056

Cited by 6 publications

(6 citation statements)

References 38 publications

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“…Moreover, 21 studies were deleted because the outcome measurement was not of interest. Ultimately, 32 eligible articles ( Liang et al, 1991 ; Meng, 2006 ; Fu, 2007 ; Liu, 2007 ; Wang, 2007 ; Wang et al, 2007 ; Zhang, 2007 ; Xu, 2008 ; Liu, 2009 ; Deng, 2010 ; Fang et al, 2012 ; Zhang et al, 2012 ; Wang, 2013 ; Zhou et al, 2013 ; Sun et al, 2014 ; Yu, 2015 ; Cui et al, 2018 ; Gao, 2018 ; Gao et al, 2018 ; Hu et al, 2018 ; Li et al, 2018 ; Zhang et al, 2018 ; Liu et al, 2019 ; Wang M. et al, 2020 ; Li et al, 2020 ; Peng et al, 2020 ; Zhang et al, 2020 ; Zhou et al, 2020 ; Xia et al, 2021 ; Yang et al, 2021 ; Ye et al, 2021 ; Wang S. et al, 2022 ) were identified for further evaluation, data extraction, and analysis ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Of them, the animals used in three studies ( Liang et al, 1991 ; Zhang et al, 2012 ; Sun et al, 2014 ) comprised Sprague–Dawley (SD) and Wistar rats, and two studies ( Deng, 2010 ; Wang, 2013 ) guinea pigs. The weight of rats ranged from 150 to 350 g, and the weight of guinea pigs ranged from 300 to 350 g. Among which, zebrafish embryos were employed in seven studies ( Fang et al, 2012 ; Cui et al, 2018 ; Liu et al, 2019 ; Wang S. et al, 2020 ; Li et al, 2020 ; Xia et al, 2021 ; Ye et al, 2021 ), H9c2 cell in nine studies ( Gao, 2018 ; Gao et al, 2018 ; Hu et al, 2018 ; Zhang et al, 2018 ; Li et al, 2020 ; Peng et al, 2020 ; Zhang et al, 2020 ; Yang et al, 2021 ; Wang W. et al, 2022 ), primary cardiomyocytes of SD rats in 10 studies ( Meng, 2006 ; Fu, 2007 ; Wang, 2007 ; Wang et al, 2007 ; Zhang, 2007 ; Xu, 2008 ; Liu, 2009 ; Zhou et al, 2013 ; Yu, 2015 ; Li et al, 2018 ), primary cardiomyocytes of Wistar rats in three studies ( Liu, 2007 ; Sun et al, 2014 ; Zhou et al, 2020 ). Meanwhile, three studies chose primary cardiomyocytes of guinea pigs ( Wang, 2013 ) and AC-16 cells ( Cui et al, 2018 ; Zhou et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…A large number of cardiomyocyte apoptosis is also considered a crucial marker for evaluating the cardiotoxicity of compounds ( Hu et al, 2018 ). In our study, the apoptosis rate was conducted in seven studies ( Gao, 2018 ; Hu et al, 2018 ; Zhang et al, 2018 ; Liu et al, 2019 ; Li et al, 2020 ; Xia et al, 2021 ; Yang et al, 2021 ). The meta-analysis of two studies ( Gao, 2018 ; Zhang et al, 2018 ) showed that compared with the control group, the apoptosis rate prominently surged and boomed in a concentration-dependent manner [ n = 18, SMD = 20.01, 95% CI (10.86 to 29.15), p < 0.0001; heterogeneity χ 2 = 1.68, df = 1 ( p = 0.20), I 2 = 40%] ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 99%

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An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Jiang

Zhang²,

Zhang³

et al. 2022

Front. Pharmacol.

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Background: Most Aconitum species in traditional Chinese medicine have the effect of dispelling wind, dehumidifying, warming the meridian, and relieving pain. Aconitine is the characteristic chemical component with the function of anti-inflammation, analgesic, and heart-strengthening effects. However, improper use will produce cardiotoxicity and neurotoxicity. Currently, the mechanisms of cardiotoxicity caused by aconitine are wheels within wheels without being fully disclosed. The systematic review and meta-analysis were therefore conducted to summarize the available evidence of myocardial toxicity caused by aconitine.Methods: We searched PubMed, Embase, Web of Science, National Knowledge Infrastructure, WANFANG, and VIP information database for relevant preclinical studies. All the data were analyzed by RevMan version 5.3.Results: Thirty-two studies met the final inclusion criteria, including both in vivo and in vitro study types. After aconitine treatment, the heart rate of animals was obviously abnormal, and the morphology and function of myocardial cells were significantly changed. Aconitine can induce changes in the electrophysiological activity of cardiac myocytes by regulating Na+, Ca2+, and K+ currents. Meanwhile, the mechanisms of cardiotoxicity of aconitine may be related to triggering mitochondrial dysfunction by inducing mitochondrial apoptosis and autophagy. It should not be ignored that the overactivation of NLRP3 inflammasome also exacerbates aconitine’s cardiotoxicity.Conclusion: The altered ion channels and mitochondrial function, as well as the signaling pathways interacting with NLRP3, may deserve further study for aconitine-induced cardiotoxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Jiang

Zhang²,

Zhang³

et al. 2022

Front. Pharmacol.

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“…The TRPV1 channel is a thermosensitive channel that can be activated by Aconitum plants and components such as capsaicin and aconitine, which in turn can induce apoptosis, Ca 2+ overload, and so on, leading to a certain degree of toxicity [ 52 – 55 ]. Some literature also suggested that one of the causes of cardiotoxicity of Caowu may also be related to the activation of TRPV1 channel [ 31 , 33 , 34 ]. Meanwhile, our experiments also proved this notion: activation of TRPV1 channel induced by MA could accelerate the generation of apoptosis, decrease the mitochondrial membrane potential, and intracellular Ca 2+ overload, which was significantly reversed by BCTC, a TRPV1 antagonist.…”

Section: Discussionmentioning

confidence: 99%

Gallic Acid Inhibits Mesaconitine-Activated TRPV1-Channel-Induced Cardiotoxicity

Han

Bao

Li³

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Aconiti Kusnezoffii Radix (Caowu) is often combined or processed with Chebulae Fructus (Hezi) to achieve attenuation purposes in Mongolian medicine. Mesaconitine (MA), a main bioactive ingredient of Caowu, is also famous for its high cardiotoxicity while exerting good anti-inflammatory and analgesic properties. Gallic acid (GA), one of the leading chemical components in Hezi, possesses cardiac protection. This study aimed to clarify the detoxification effects of GA from Hezi on MA-induced cardiotoxicity and whether the detoxification mechanism is related to the TRPV1 channel. Cell viability was determined by methyl thiazol tetrazolium (MTT), and lactate dehydrogenase (LDH) leakage rate was determined by ELISA. Hoechst 33258, JC-1, DCFH-DA, and Fluo-3 AM staining were conducted to detect apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS), and Ca2+ respectively; TRPV1 channel current was recorded by whole-cell patch-clamp technology to observe the effect of GA and MA alone or in combination on TRPV1 channel. The results showed that GA exhibited pronounced detoxification effects on MA-induced cardiotoxicity. GA significantly inhibited the MA-induced decrease in cell viability; suppressed the MA-induced LDH leakage rate, apoptosis, and the release of ROS and Ca2+; and alleviated the reduction of mitochondrial membrane potential. We found that MA-induced cardiotoxicity was significantly attenuated in H9c2 cells pretreated with the TRPV1 antagonist BCTC. In the whole-cell patch-clamp experiment, the TRPV1 channel current increase was caused by the GA and MA treatment, whereas it was reduced by the cotreatment of GA and MA. Our data demonstrate that GA in Hezi can reduce MA-induced cardiotoxicity by inhibiting intracellular Ca2+ influx, restoring mitochondrial membrane potential, and reducing apoptosis. The detoxification mechanism may be related to the desensitization of the TRPV1 channel by the combined application of MA and GA.

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“…Among them, ion channels are an important way to exert the efficacy and toxicity of diester alkaloids. When the function of ion channels is aberrant, the proportion of each channel in the myocardium will be destroyed, which will induce cardiac diseases such as arrhythmia ( Fu et al, 2007 ; Yang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

Song,

Mi,

Zhao

et al. 2024

Front. Pharmacol.

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Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation.Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel.Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine.Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.

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

Cited by 6 publications

References 38 publications

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Gallic Acid Inhibits Mesaconitine-Activated TRPV1-Channel-Induced Cardiotoxicity

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel

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