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Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2?/ATF4/Chop pathway.

ABSTRACT: Fuziline, an aminoalcohol-diterpenoid alkaloid derived from Aconiti lateralis radix preparata, has been reported to have a cardioprotective activity in vitro. However, the potential mechanism of fuziline on myocardial protection remains unknown. In this study, we aimed to explore the efficacy and mechanism of fuziline on isoproterenol (ISO)-induced myocardial injury in vitro and in vivo. As a result, fuziline effectively increased cell viability and alleviated ISO-induced apoptosis. Meanwhile, fuziline significantly decreased the production of ROS, maintained mitochondrial membrane potential (MMP) and blocked the release of cytochrome C, suggesting that fuziline could play the cardioprotective role through restoring the mitochondrial function. Fuziline also could suppress ISO-induced endoplasmic reticulum (ER) stress via the PERK/eIF2?/ATF4/Chop pathway. In addition, using ROS scavenger NAC could decrease ISO-induced apoptosis and block ISO-induced ER stress, while PERK inhibitor GSK2606414 did not reduce the production of ROS, indicating that excess production of ROS induced by ISO triggered ER stress. And fuziline protected against ISO-induced myocardial injury by inhibiting ROS-triggered ER stress. Furthermore, fuziline effectively improved cardiac function on ISO-induced myocardial injury in rats. Western blot analysis also showed that fuziline reduced ER stress-induced apoptosis in vivo. Above these results demonstrated that fuziline could reduce ISO-induced myocardial injury in vitro and in vivo by inhibiting ROS-triggered ER stress via the PERK/eIF2?/ATF4/Chop pathway.

SUBMITTER: Fan CL

PROVIDER: S-EPMC6991694 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway.

Fan Cai-Lian CL Yao Zhi-Hong ZH Ye Meng-Nan MN Fu Lei-Lei LL Zhu Guo-Nian GN Dai Yi Y Yao Xin-Sheng XS

Journal of cellular and molecular medicine 20191207 2

Fuziline, an aminoalcohol-diterpenoid alkaloid derived from Aconiti lateralis radix preparata, has been reported to have a cardioprotective activity in vitro. However, the potential mechanism of fuziline on myocardial protection remains unknown. In this study, we aimed to explore the efficacy and mechanism of fuziline on isoproterenol (ISO)-induced myocardial injury in vitro and in vivo. As a result, fuziline effectively increased cell viability and alleviated ISO-induced apoptosis. Meanwhile, f ...[more]

PMID: 31811750

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Project description:It has been reported that ginsenoside Rg1 (G‑Rg1) can alleviate alcoholic liver injury, cardiac hypertrophy and myocardial ischemia, as well as reperfusion injury. Therefore, the present study aimed to investigate the role of G‑Rg1 in alcohol‑induced myocardial injury, as well as to elucidate its underlying mechanisms of action. For this purpose, H9c2 cells were stimulated with ethanol. Subsequently, H9c2 cell viability and apoptosis were determined using a Cell Counting Kit‑8 assay and flow cytometric analysis, respectively. The levels of lactate dehydrogenase and caspase‑3 in the H9c2 cell culture supernatant were detected using corresponding assay kits. In addition, the expression of green fluorescent protein (GFP)‑light chain 3 (LC3) and that of C/EBP homologous protein (CHOP) were evaluated using GFP‑LC3 assay and immunofluorescence staining, respectively. The expression levels of apoptosis‑, autophagy‑, endoplasmic reticulum stress (ERS)‑ and adenosine 5'‑monophosphate‑activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway‑related proteins were detected using western blot analysis. The results revealed that treatment with G‑Rg1 enhanced the viability and suppressed the apoptosis of ethanol‑stimulated H9c2 cells. G‑Rg1 also attenuated autophagy and ERS in ethanol‑stimulated H9c2 cells. In addition, the levels of phosphorylated (p)‑protein kinase R (PKR)‑like ER kinase (PERK), p‑eukaryotic translation initiation factor 2a, activating transcription factor 4 (ATF4), CHOP, caspase‑12 and p‑AMPK were downregulated, while the p‑mTOR level was upregulated in ethanol‑stimulated H9c2 cells treated with G‑Rg1. Furthermore, the co‑treatment of G‑Rg1‑treated ethanol‑stimulated H9c2 cells with AICAR, an AMPK agonist, or CCT020312, a PERK agonist, inhibited cell viability and promoted cell apoptosis, autophagy and ERS. Overall, the results of the present study suggest that G‑Rg1 suppresses autophagy and ERS via inhibiting the AMPK/mTOR and PERK/ATF4/CHOP pathways to alleviate ethanol‑induced H9c2 cell injury.

Project description:BackgroundDue to the abnormal angiogenesis, cancer stem cells (CSCs) in esophageal cancer (EC) have the characteristics of a hypoxic microenvironment. However, they can resist hypoxia-induced apoptosis. the molecular mechanism underlying the resistance of esophageal CSCs to hypoxia-induced apoptosis is currently unclear. Therefore, this study will investigate the molecular mechanism based on CHOP-mediated endoplasmic reticulum stress.MethodsCD44+CD24- cells in EC9706 cells were screened by fluorescence-activated cell sorting (FACS). To clarify which apoptosis pathway esophageal CSCs resist hypoxia-induced cell apoptosis through, the effects of hypoxia on apoptosis were detected by nuclear staining, flow cytometry, and JC-1 reagent, the effects of hypoxia on the expression of apoptosis-related proteins were detected by western blotting (WB) assay and quantitative polymerase chain reaction (qPCR) assay. To clarify the mechanisms of CD44+CD24- cells resistance to hypoxia-induced apoptosis is achieved by inhibiting the activation of endoplasmic reticulum stress (ERS) pathway, silenced CHOP and PERK cell lines of EC9706 cells and overexpressed CHOP and PERK cell lines of CD44+CD24- cells were constructed, the effects of hypoxia on apoptosis, cell cycle, and mitochondrial membrane potential were detected by flow cytometry and JC-1 reagent. WB assay and qPCR assay were used to detect the expressions of apoptosis-related proteins and ERS-related proteins.ResultsHypoxia significantly induce apoptosis and cycle arrest of EC9706 cells (P<0.05), but did not affect apoptosis and cycle of CD44+CD24- cells (P>0.05). Hypoxia considerably induced the activation of mitochondrial and ERS apoptosis pathways in EC9706 cells (P<0.05), but did not affect Fas receptor apoptosis pathways (P>0.05). The three apoptosis pathways were not affected by hypoxia in CD44+CD24- cells (P>0.05). Silencing the CHOP and PERK gene inhibited hypoxia-induced apoptosis of EC9706 cells (P<0.05). CHOP and PERK overexpression promoted hypoxia-induced apoptosis of CD44+CD24- cells (P<0.05), whereas mitochondrial membrane permeability inhibitors inhibited hypoxia-induced apoptosis of CD44+CD24- cells overexpressed CHOP gene.ConclusionsCD44+CD24- tumor stem cells in EC resist to hypoxia-induced apoptosis by the inhibition of ERS-mediated mitochondrial apoptosis pathway, which suggested that ERS pathway can serve as a potential target for reducing EC treatment resistance in clinical treatment.

Dataset Information

Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2?/ATF4/Chop pathway.

Publications

Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway.

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