Mechanisms underlying astrocytic connexin-43 autophagy degradation during cerebral ischemia injury and the effect on neuroinflammation and cell apoptosis

Wang, Xinyu; Feng, Lei; Xin, Meiying; Hao, Yulei; Wang, Xu; Shang, Pei; Zhao, Mingming; Hou, Shuxun; Zhang, Yunhai; Xiao, Yun; Ma, Di; Feng, Jiachun

doi:10.1016/j.biopha.2020.110125

Cited by 25 publications

(20 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cx43 plays a significant role in cell growth, proliferation and apoptosis. Recently, a study showed that Cx43 gene knockout or accelerated degradation protected astrocytes from apoptosis under ischemic stress ( Wang X. et al, 2020 ). Ma JW et al found that Cx43 inhibition attenuated oxidative stress and apoptosis in HUVECs ( Ma et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Adiponectin Attenuates Lipopolysaccharide-induced Apoptosis by Regulating the Cx43/PI3K/AKT Pathway

et al. 2021

View full text Add to dashboard Cite

Cardiomyocyte apoptosis is a crucial factor leading to myocardial dysfunction. Adiponectin (APN) has a cardiomyocyte-protective impact. Studies have shown that the connexin43 (Cx43) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathways play an important role in the heart, but whether APN plays a protective role by regulating these pathways is unclear. Our study aimed to confirm whether APN protects against lipopolysaccharide (LPS)-induced cardiomyocyte apoptosis and to explore whether it plays an important role through regulating the Cx43 and PI3K/AKT signaling pathways. In addition, our research aimed to explore the relationship between the Cx43 and PI3K/AKT signaling pathways. In vitro experiments: Before H9c2 cells were treated with LPS for 24 h, they were pre-treated with APN for 2 h. The cytotoxic effect of APN on H9c2 cells was evaluated by a CCK-8 assay. The protein levels of Bax, Bcl2, cleaved caspase-3, cleaved caspase-9, Cx43, PI3K, p-PI3K, AKT and p-AKT were evaluated by Western blot analysis, and the apoptosis rate was evaluated by flow cytometry. APN attenuated the cytotoxicity induced by LPS. LPS upregulated Bax, cleaved caspase-3 and cleaved caspase-9 and downregulated Bcl2 in H9c2 cells; however, these effects were attenuated by APN. In addition, LPS upregulated Cx43 expression, and APN downregulated Cx43 expression and activated the PI3K/AKT signaling pathway. LPS induced apoptosis and inhibited PI3K/AKT signaling pathway in H9c2 cells, and these effects were attenuated by Gap26 (a Cx43 inhibitor). Moreover, the preservation of APN expression was reversed by LY294002 (a PI3K/AKT signaling pathway inhibitor). In vivo experiments: In C57BL/6J mice, a sepsis model was established by intraperitoneal injection of LPS, and APN was injected into enterocoelia. The protein levels of Bax, Bcl2, cleaved caspase-3, and Cx43 were evaluated by Western blot analysis, and immunohistochemistry was used to detect Cx43 expression and localization in myocardial tissue. LPS upregulated Bax and cleaved caspase-3 and downregulated Bcl2 in sepsis; however, these effects were attenuated by APN. In addition, the expression of Cx43 was upregulated in septic myocardial tissue, and APN downregulated Cx43 expression in septic myocardial tissue. In conclusion, both in vitro and in vivo, the data demonstrated that APN can protect against LPS-induced apoptosis during sepsis by modifying the Cx43 and PI3K/AKT signaling pathways.

show abstract

Section: Discussionmentioning

confidence: 99%

Adiponectin Attenuates Lipopolysaccharide-induced Apoptosis by Regulating the Cx43/PI3K/AKT Pathway

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Suppressing the ubiquitination of Cx43 could repair the neuroinflammatory process theoretically. It is well documented that inhibiting Cx43 degradation promoted glial cells transformed into an anti-inflammatory status ( Huang et al, 2019 ; Wang et al, 2020 ). Conversely, the acceleration of Cx43 degradation triggered the inflammatory process.…”

Section: Discussionmentioning

confidence: 99%

“…According to the previous reports, Rg1 could rescue stress-induced depression-like behaviors via inhibition of inflammation ( Li et al, 2020b ). Multiple studies demonstrated that inhibiting the degradation of Cx43 promoted glial cells translating from a pro-inflammatory to an anti-inflammatory status ( Huang et al, 2019 ; Wang et al, 2020 ). Besides, Cx43 degradation during stress requires its ubiquitination ( Xia et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rg1 Ameliorates Neuroinflammation via Suppression of Connexin43 Ubiquitination to Attenuate Depression

Wang

Yang

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Depression is an inflammation-associated disease that results in major depression as inflammation increases and progresses. Ginsenoside Rg1 (Rg1), the major bioactive ingredient derived from ginseng, possesses remarkable anti-depressant and anti-inflammatory effects. Our previous studies showed that the pathogenesis of depression was concomitant with the acceleration of connexin43 (Cx43) ubiquitin degradation, while Rg1 could upregulate Cx43 expression to attenuate depression. However, whether the ubiquitination of Cx43 is the specific correlation between depression and inflammation, and how Rg1 ameliorates neuroinflammation to attenuate depression, are still under investigation. In in vivo experiments, Rg1 treatment significantly ameliorated depression-like behaviors in rats subjected to chronic unpredictable stress (CUS). Moreover, these CUS rats treated with Rg1 exhibited attenuated neuroinflammation, together with the suppression of Cx43 ubiquitination. In in vitro experiments, Rg1 reduced the secretion of inflammatory cytokines and the ubiquitination of Cx43 in lipopolysaccharide-induced glial cells. Furthermore, treatment with ubiquitin-proteasome inhibitor MG132 suppressing the ubiquitination of Cx43 ameliorated lipopolysaccharide-induced neuroinflammation. The results suggest that Rg1 attenuates depression-like behavioral performances in CUS-exposed rats; and the main mechanism of the antidepressant-like effects of Rg1 appears to involve protection against neuroinflammation via suppression of Cx43 ubiquitination. In conclusion, Rg1 could ameliorate neuroinflammation via suppression of Cx43 ubiquitination to attenuate depression, which represents the perspective of an innovative therapy of Rg1 in the treatment of inflammation-associated depression.

show abstract

“…Inhibition of Cx43 autophagic degradation is conducive to the transformation of astrocytes from pro-inflammatory state to anti-inflammatory state, so as to prevent anti-inflammatory reactions during ischemia. In addition, under ischemic stress, depletion of Cx43 or acceleration of its degradation in astrocytes can fully protect cells from apoptosis [38]. Furthermore, ischemic preconditioning can effectively block the gap between astrocytes, reduce extracellular glutamate, reduce the release of glutamate and reactive oxygen species ROS in astrocytes, and reduce neuronal injury [37].…”

Section: Astrocytes In Ischemic Brainmentioning

confidence: 99%

Function of Astrocytes in Neuroprotection and Repair after Ischemic Stroke

et al. 2021

View full text Add to dashboard Cite

Background: Astrocytes are the most numerous cell types within the central nervous system, and many efforts have been put into determining the exact role of astrocytes in neuroprotection and repair after ischemic stroke. Although numerous studies have been done in recent years, there is still no thorough understanding of the exact function of astrocytes in the whole course of the stroke. Summary: According to the recent literature, there are many structures and factors that play important roles in the process of ischemic stroke, among which blood-brain barrier, various growth factors, gap junctions, AQP4, and glial scars have been studied most comprehensively, and all these factors are closely related to astrocytes. The role of astrocytes in ischemic stroke, therefore, can be analyzed more comprehensively. Key Message: The present review mainly summarized the current knowledge about astrocytes and their potential roles after ischemic stroke.

show abstract

Mechanisms underlying astrocytic connexin-43 autophagy degradation during cerebral ischemia injury and the effect on neuroinflammation and cell apoptosis

Cited by 25 publications

References 58 publications

Adiponectin Attenuates Lipopolysaccharide-induced Apoptosis by Regulating the Cx43/PI3K/AKT Pathway

Adiponectin Attenuates Lipopolysaccharide-induced Apoptosis by Regulating the Cx43/PI3K/AKT Pathway

Ginsenoside Rg1 Ameliorates Neuroinflammation via Suppression of Connexin43 Ubiquitination to Attenuate Depression

Function of Astrocytes in Neuroprotection and Repair after Ischemic Stroke

Contact Info

Product

Resources

About