Gap Junction Intercellular Communication Negatively Regulates Cadmium-Induced Autophagy and Inhibition of Autophagic Flux in Buffalo Rat Liver 3A Cells

Zou, Hui; Yuan, Junzhao; Zhang, Yi; Wang, Tao; Chen, Yan; Yuan, Yan; Bian, Jianchun; Liu, Zongping

doi:10.3389/fphar.2020.596046

Cited by 11 publications

(8 citation statements)

References 47 publications

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“…In addition, we can also explore the role of gap junction intercellular communication (GJIC) function in VSMC autophagy. It has been found that GJIC negatively regulated autophagy and inhibited autophagy flux ( Zou et al, 2020 ). In summary, ox-LDL prevented VSMC autophagy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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Background Oxidized low-density lipoproteins (ox-LDL) may induce foam cell formation from the vascular smooth muscle cell (VSMC) by inhibiting VSMC autophagy. This process accelerates the formation of atherosclerosis (AS). Connexin 43 (Cx43), which is the most widely distributed connexin in VSMC is associated with autophagy. However, the mechanism of action and the involvement of Cx43 in ox-LDL-inhibited VSMC autophagy remain unclear. Methods The primary VSMC were obtained and identified, before primary VSMC were pretreated with an inhibitor (Cx43-specific inhibitor Gap26 and PI3K inhibitor LY294002) and stimulated with ox-LDL. Results Ox-LDL not only inhibited autophagy in VSMC via downregulation of autophagy-related proteins (such as Beclin 1, LC3B, p62), but also increased Cx43 protein levels. Then we added Gap26 to VSMC in the ox-LDL+Gap26 group, in which autophagy-related proteins were increased and the accumulation of lipid droplets was reduced. These result suggested that an enhanced level of autophagy and an alleviation of lipid accumulation might be caused by inhibiting Cx43 in VSMC. The phosphorylation levels of PI3K, AKT, mTOR were increased by ox-LDL, thus down-regulating autophagy-related proteins. However, this situation was partially reversed by the Gap26. Moreover, Cx43 expression were decreased by LY294002 in ox-LDL-induced VSMCs. Conclusion Inhibiting Cx43 may activate VSMC autophagy to inhibit foam cell formation by inhibiting the PI3K/AKT/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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“…Autophagy is a dynamic and complex process; impairment of any of its elements can impact autophagic flux. Cd elevates the level of autophagy in rat BRL3A cells [ 30 ] and results in higher levels of autophagy and blocked autophagic flux in mouse hepatocytes AML12 cells [ 29 ]. Ni Gao et al [ 31 ] found that Tau can inhibit hepatic autophagy by activating the PPARγ-mTORC2 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…BRL3A cells were seeded in 24-well plates and cultured to approximately 80% confluence, followed by treatment with 80 mM Tau and/or 5 μM Cd for 6 h. Then, cells were photographed with the Leica DMIRB inverted microscope. The doses of Cd and Tau were determined based on previous studies [ 30 , 41 , 42 , 43 ]. While referring to the previous studies, we also screened the concentration of Tau, and finally 80 mM Tau was used to treat the cells in this experiment.…”

Section: Methodsmentioning

confidence: 99%

Taurine Alleviates Cadmium-Induced Hepatotoxicity by Regulating Autophagy Flux

Duan

Zhao

Wang

et al. 2023

IJMS

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Our previous studies have confirmed that cadmium (Cd) exposure causes hepatotoxicity; it also induces autophagy and blocks the autophagy flux. Therefore, we hypothesized that Cd hepatotoxicity could be alleviated through nutritional intervention. Taurine (Tau) has various biological functions such as acting as an antioxidant, acting as an anti−inflammatory, and stabilizing cell membranes. In order to explore the protective effect and internal mechanism of Tau on Cd−induced hepatotoxicity, normal rat liver cell line BRL3A cells were treated with Cd alone or in combination with Tau to detect cell injury and autophagy−related indexes in this study. We found that Tau can alleviate Cd−induced cell−proliferation decline and morphological changes in the cell. In addition, Tau activates autophagy and alleviates the blockage of Cd−induced autophagy flux. In this process, lysosome acidification and degradation were enhanced, and autophagosomes were further fused with lysosomes. Then, we found that Tau alleviated autophagic flux block by promoting the transfer of membrane fusion proteins STX17 and SNAP29 to autophagosomes and the translocation of VAMP8 to lysosomes, which in turn attenuated the hepatocyte injury induced by Cd exposure. This will further reveal the hepatotoxicity mechanism of Cd and provide the theoretical basis for the prevention and treatment of Cd poisoning.

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“…The Cd-induced decrease in Cx43 levels in BRL 3A cells as well as the internalization and degradation of Cx43 may have blocked the transmission of toxins between cells through gap junctions. Previously, other members of our group used 18β-glycyrrhetinic acid, a compound that promoted Cx43 internalization, to alleviate the damage caused by Cd exposure to rat hepatocytes [ 52 ]. The results from the present study are concordant with their results.…”

Section: Discussionmentioning

confidence: 99%

Rat Hepatocytes Mitigate Cadmium Toxicity by Forming Annular Gap Junctions and Degrading Them via Endosome–Lysosome Pathway

Yuan

Huang

Zhao

et al. 2022

IJMS

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Gap junction protein connexin 43 (Cx43) plays a critical role in gap junction communication in rat hepatocytes. However, those located between hepatocytes are easily internalized following exposure to poisons. Herein, we investigated the potential of buffalo rat liver 3A (BRL 3A) cells to generate annular gap junctions (AGJs) proficient at alleviating cadmium (Cd) cytotoxic injury through degradation via an endosome–lysosome pathway. Our results showed that Cd-induced damage of liver microtubules promoted Cx43 internalization and increased Cx43 phosphorylation at Ser373 site. Furthermore, we established that Cd induced AGJs generation in BRL 3A cells, and AGJs were subsequently degraded through the endosome–lysosome pathway. Overall, our results suggested that Cx43 internalization and the generation of AGJs were cellular protective mechanisms to alleviate Cd toxicity in rat hepatocytes.

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Gap Junction Intercellular Communication Negatively Regulates Cadmium-Induced Autophagy and Inhibition of Autophagic Flux in Buffalo Rat Liver 3A Cells

Cited by 11 publications

References 47 publications

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Taurine Alleviates Cadmium-Induced Hepatotoxicity by Regulating Autophagy Flux

Rat Hepatocytes Mitigate Cadmium Toxicity by Forming Annular Gap Junctions and Degrading Them via Endosome–Lysosome Pathway

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