The role of the cholinergic anti-inflammatory pathway in septic cardiomyopathy

Wang, Wenting; Xu, Hui; Lin, Huan; Molnar, Megan E.; Ren, Hongsheng

doi:10.1016/j.intimp.2020.107160

Cited by 25 publications

(19 citation statements)

References 92 publications

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“…Sepsis often induces varying degrees of cardiac dysfunction, thereby resulting in a poor prognosis [ 3 ]. In 1984, Parker et al [ 4 ] discovered reversible cardiac dysfunction in septic patients and proposed the concept of sepsis-induced cardiomyopathy (SIC), the major cause of death in septic patients [ 5 ]. To date, the pathogenesis of SIC remains elusive [ 6 ], which involves a few of factors such as inflammatory damage, myocardial mitochondrial dysfunction, and oxidative stress injury [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Macrophage-Derived Exosomes in TLR9-/- Mice Ameliorate Sepsis-Induced Mitochondrial Oxidative Stress and Apoptosis in Cardiomyocytes

Luo

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. To explore the mechanisms of TLR9 from macrophages on mitochondrial apoptosis in cardiomyocytes at early stage of sepsis. Methods. The in vivo and in vitro sepsis mice were bone marrow transplantation (BMT) with wild type (WT) or (toll-like receptor 9) TLR9 knockout (-/- or KO) myeloid cells and then constructed by cecum ligation and puncture (CLP) as vivo experiment and cardiomyocytes cocultured with WT or TLR9-deficient macrophages treated with LPS as vitro experiment, respectively. Sepsis model were performed by CLP. The expression levels of exosome, PI3K/AKT, and ERK1/2, inflammatory factors, and apoptotic proteins were tested by western blot in vivo. Besides, associated apoptotic proteins and JC-1 fluorescence assay were tested in vitro. Results. The expressions of p-PI3K, p-AKT, exosome markers (CD9, CD63, and TSG101), p-ERK1/2, TNF-α, IFN-γ, IL-1β, and cleaved-caspase-3/-9 were significantly increased in septic mice vs. control mice, and these proteins were declined dramatically in TLR9-/- BMT mice vs. WT BMT mice in sepsis mice models. Meanwhile, the protein expression of cytochrome C, cleaved-caspase-3, and cleaved-caspase-9 increased significantly in primary mouse myocardial cells cocultured with TLR9-/- or WT macrophages stimulated with LPS, and these mitochondrial apoptotic proteins as well as the green 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolcarbocyanine iodide (JC-1) fluorescence were dramatically lower in LPS-stimulated cardiomyocytes cocultured with TLR9-/- than with WT macrophages. Conclusion. TLR9-/- in macrophages suppressed the inflammatory reaction as well as the exosome secretion and resulted in the inhibition of apoptosis and oxidative stress in sepsis-induced cardiomyopathy.

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Section: Introductionmentioning

confidence: 99%

Macrophage-Derived Exosomes in TLR9-/- Mice Ameliorate Sepsis-Induced Mitochondrial Oxidative Stress and Apoptosis in Cardiomyocytes

Luo

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…[24] The cholinergic pathway may also be targeted for pain inhibition by inducing an anti-in ammatory effect. [25] Current ndings suggest that combining choline and parecoxib sodium, which have different properties, may improve neuropathic pain inhibition and decrease the side effects of each drug by reducing the required dose. This notion needs to be further tested in future clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Choline and Parecoxib Sodium Induced Pain Inhibition in Rats After Chronic Constriction Injury of the Sciatic Nerve

Zhang

Yang

Feng

2022

Preprint

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Purpose We aimed to examine the pain inhibitory effects of systemic administration of choline and parezoxib sodium in a rat model of neuropathic pain induced by a chronic constriction injury (CCI) of the sciatic nerve, and to determine the changes of high mobility protein-1 (HMGB1) and NF-κBp65 expression in the dorsal root ganglion (DRG) after drug treatment. Methods Adult rats were randomly divided into 5 groups (N = 8/group). Sham surgery group received an intraperitoneal (i.p.) injection of saline. CCI rats received saline, choline (cho, 6, 12 and 24 mg/kg), parecoxib sodium (pare, 3, 6, 12mg/kg), or a combination of choline and parecoxib sodium with each drug delivered at a sub-effective dose. Mechanical and heat pain thresholds were measured at 30 min after drug treatment at day 3, 5, 7, 10, and 14 after CCI. In a separate study, rats were also divided into 5 groups (N = 6/group) including sham, CCI + saline, CCI + cho-6 mg/kg, CCI + pare-3mg/kg, and CCI + cho-6mg/kg + pare-3mg/kg group. After repeated drug treatment for 7 days, five rats were randomly selected in each group, and the lumbar DRGs (L4-6) were harvested for Western blot study. Results Choline significantly attenuated the mechanical and heat hypersensitivities in CCI rats at 12 and 24 mg/kg doses (P < 0.05), but was not effective at 6 mg/kg dose. Parecoxib sodium exerted significant pain inhibitory effects at 6 and 12 mg/kg doses (P < 0.05), but not at 3 mg/kg dose. Combining a low dose of choline (6 mg/kg) and parecoxib sodium (3 mg/kg) produced significant pain inhibition in CCI rats, and also reduced the expression of HMGB1 and NF-κBp65 in L4-6 DRGs. Conclusion A combination of choline and parecoxib sodium may effectively relieve neuropathic pain, and the underlying mechanisms may involve an inhibition of HMGB1/TLR4/NF-κB signaling pathway in DRG neurons.

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“…We subsequently explored the diagnostic capability and prognostic relevance of key genes for sepsis in whole blood transcriptomic data from independent cohorts. In addition, given the close association between SCM and the immune response, we performed immune correlation analysis on the identified key genes ( 8 , 31 ). Finally, we predicted potential therapeutic drugs based on key genes for further exploration.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated autophagy-related genes in septic cardiomyopathy: Comprehensive bioinformatics analysis based on the human transcriptomes and experimental validation

Zou

Qiu

Zhang

et al. 2022

Front. Cardiovasc. Med.

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Septic cardiomyopathy (SCM) is severe organ dysfunction caused by sepsis that is associated with poor prognosis, and its pathobiological mechanisms remain unclear. Autophagy is a biological process that has recently been focused on SCM, yet the current understanding of the role of dysregulated autophagy in the pathogenesis of SCM remains limited and uncertain. Exploring the molecular mechanisms of disease based on the transcriptomes of human pathological samples may bring the closest insights. In this study, we analyzed the differential expression of autophagy-related genes in SCM based on the transcriptomes of human septic hearts, and further explored their potential crosstalk and functional pathways. Key functional module and hub genes were identified by constructing a protein–protein interaction network. Eight key genes (CCL2, MYC, TP53, SOD2, HIF1A, CTNNB1, CAT, and ADIPOQ) that regulate autophagy in SCM were identified after validation in a lipopolysaccharide (LPS)-induced H9c2 cardiomyoblast injury model, as well as the autophagic characteristic features. Furthermore, we found that key genes were associated with abnormal immune infiltration in septic hearts and have the potential to serve as biomarkers. Finally, we predicted drugs that may play a protective role in SCM by regulating autophagy based on our results. Our study provides evidence and new insights into the role of autophagy in SCM based on human septic heart transcriptomes, which would be of great benefit to reveal the molecular pathological mechanisms and explore the diagnostic and therapeutic targets for SCM.

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The role of the cholinergic anti-inflammatory pathway in septic cardiomyopathy

Cited by 25 publications

References 92 publications

Macrophage-Derived Exosomes in TLR9-/- Mice Ameliorate Sepsis-Induced Mitochondrial Oxidative Stress and Apoptosis in Cardiomyocytes

Macrophage-Derived Exosomes in TLR9-/- Mice Ameliorate Sepsis-Induced Mitochondrial Oxidative Stress and Apoptosis in Cardiomyocytes

Choline and Parecoxib Sodium Induced Pain Inhibition in Rats After Chronic Constriction Injury of the Sciatic Nerve

Dysregulated autophagy-related genes in septic cardiomyopathy: Comprehensive bioinformatics analysis based on the human transcriptomes and experimental validation

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