Fuziline alleviates isoproterenol‐induced myocardial injury by inhibiting ROS‐triggered endoplasmic reticulum stress via PERK/eIF2α/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/eIF2α/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/eIF2α/ATF4/Chop pathway. K E Y W O R D Sapoptosis, ER stress, fuziline, isoproterenol, ROS | 1333 FAN et Al.

Aconitum Diterpenoid Alkaloid Profiling to Distinguish between the Official Traditional Chinese Medicine (TCM) Fuzi and Adulterant Species Using LC-qToF-MS with Chemometrics

“…12 Wsczukidine (7) and miyaconitine (10) have been identified as chemical markers for this species (Figure 8D). The marker for A. transsectum detected in the study, 14-acetyltalatisamine (17), was also isolated and reported from this species by other groups previously. 5,20−22 These 10 selected markers were shown to be present in "high content" in the species as all their Y-axis values exceeded 1000.…”

“…For example, fuziline has reported cardioprotective activity in vitro and in vivo. 17 Because these four markers are rarely present in other tissues of A. carmichaelii or related species, its lateral root (i.e., fuzi) has been used in traditional medicine, and the other parts (e.g., flowers, stem, or stems) are seldomly used. 1 Similarly, markers present in cluster A (Figure 4, bottom) were identified as carmichaenines D (21), C ( 22), (−)-(A-b)-14α-benzoyloxy-N-ethyl-1α, 8β, 15α-trihydroxy-16β, 18-dimethoxyaconitane (24), and 14-benzoylneoline (41), which are markers for flowers of A. carmichaelii.…”

“…Benzoylmesaconine ( 25 ) is an MDA, and fuziline ( 6 ) is an NDA, representing two additional fuzi markers in the current study; they are likely responsible for some of the bioactivities of fuzi. For example, fuziline has reported cardioprotective activity in vitro and in vivo …”

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

“…Additionally, ATF4 increases the production of ROS, which can also be proapoptotic. The importance of ATF4 was demonstrated by blocking its transcription, which promoted apoptosis [43,44]. In contrast, translation of CHOP stimulates the transcription of protein phosphatase 1 regulatory subunit 15 (PPP1R15A/GADD34), TNF-related apoptosis-inducing ligand (TRAIL2), tribbles homolog 3 (TRB3), and, as a consequence, endoplasmic reticulum disulphide oxidase 1α (Ero1α).…”

Pharmacological Disruption of Phosphorylated Eukaryotic Initiation Factor-2α/Activating Transcription Factor 4/Indian Hedgehog Protects Intervertebral Disc Degeneration via Reducing the Reactive Oxygen Species and Apoptosis of Nucleus Pulposus Cells

“…ATF4 overexpression can trigger a cascade of ROS and induce apoptosis ( Wortel et al, 2017 ; Zong et al, 2017 ). On the contrary, the disorder of ATF4 alleviates the ROS production and apoptotic process in various tissues and cell types ( Fan et al, 2020 ). As an upstream of ATF4, the phosphorylation of eukaryotic initiation factor-2α (eIF2α) preferentially facilitates the ATF4 activation, which transduces signals to the cytoplasm and nucleus to cause the imbalance of cellular homeostasis ( Harding et al, 2003 ; Liu and Zhang, 2020 ).…”