Inhibition of 5-lipoxygenase is associated with downregulation of the leukotriene B4 receptor 1/ Interleukin-12p35 pathway and ameliorates sepsis-induced myocardial injury

Xie, Sai‐Sai; Qi, Xiping; Wu, Qin; Li, Wei; Zhang, Min; Xing, Yun; Shi, Wenke; Chen, Si; Zeng, Xiaofeng; Wang, Shasha; Guo, Haipeng; Deng, Wen-feng

doi:10.1016/j.freeradbiomed.2021.02.034

Cited by 21 publications

(16 citation statements)

References 44 publications

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“…Upregulation of ALOX5 has been shown to induce LT production in human DCs treated with lipopolysaccharide [ 36 ]. Moreover, overexpression of ALOX5 accelerated myocardial injury and cardiac dysfunction in a sepsis mouse model [ 37 ]. A study showed that inhibition of ALOX5 improved functional recovery in a rat model of cerebral ischemia [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Expression Profile of Inflammation Response Genes and Potential Regulatory Mechanisms in Dilated Cardiomyopathy

Liang

Sun

Teng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. The inflammatory response is important in dilated cardiomyopathy (DCM). However, the expression of inflammatory response genes (IRGs) and regulatory mechanisms in DCM has not been well characterized. Methods. We analyzed 27,665 cells of single-cell RNA sequencing dataset of four DCM samples and two healthy controls (HC). IRGs among differentially expressed genes (DEGs) of active cell clusters were screened from the Molecular Signatures Database (MSigDB). The bulk sequencing dataset of 166 DCM patients and 166 HC was analyzed to explore the common IRGs. The biological functions of the IRGs were analyzed according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. IRG-related transcription factors (TFs) were determined using the TRRUST database. The protein–protein interaction (PPI) network was constructed using the STRING database. Then, we established the noncoding RNA (ncRNA) regulatory network based on the StarBase database. Finally, the potential drugs that target IRGs were explored using the Drug Gene Interaction Database (DGIdb). Results. The proportions of dendritic cells (DCs), B cells, NK cells, and T cells were increased in DCM patients, whereas monocytes were decreased. DCs expressed more IRGs in DCM. The GO and KEGG analyses indicated that the functional characteristics of active cells mainly focused on the immune response. Thirty-nine IRGs were commonly expressed among active cell cluster DEGs, bulk RNA DEGs, and inflammatory response-related genes. ETS1 plays an important role in regulation of IRG expression. The competing endogenous RNA regulatory network showed the relationship between ncRNA and IRGs. Sankey diagram showed that arachidonate 5-lipoxygenase (ALOX5) played a major role in regulation between TFs and potential drugs. Conclusion. DCs infiltrate into the myocardium and contribute to the immune response in DCM. The transcription factor ETS1 plays an important role in regulation of IRGs. Moreover, ALOX5 may be a potential therapeutic target for DCM.

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Section: Discussionmentioning

confidence: 99%

Expression Profile of Inflammation Response Genes and Potential Regulatory Mechanisms in Dilated Cardiomyopathy

Liang

Sun

Teng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…PGE2 and TXB2 are derived from the bioconversion of polyunsaturated fatty acids and arachidonic acid through COX-2-mediated catalysis ( Alhouayek and Muccioli, 2014 ). Previous studies have determined the positive effects of NO, PGE2 and TXB2 on facilitating inflammation progression, and reductions in the contents of these factors were proven to be effective at ameliorating sepsis-induced inflammatory reactions ( Bitto et al, 2012 ; I. Chen et al, 2018 ; Jia et al, 2018 ; Xie et al, 2021 ). Then, we found that increased levels of IL-6, TNF- α , NO, PGE2, and TXB2 produced by RAW 264.7 cells exposed to LPS were reversed by harmine treatment, implying potent drug-related anti-inflammatory actions.…”

Section: Discussionmentioning

confidence: 99%

Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway

Ruan

Qin

et al. 2022

Front. Cell Dev. Biol.

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Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which is termed sepsis-induced cardiomyopathy (SIC). Harmine, a natural β-carboline alkaloid compound, has been shown to exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, the expression of the M1 phenotype markers iNOS and COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect was reversed by the harmine intervention. Furthermore, LPS-induced increases in the levels of inflammatory cytokines, including IL-1β, IL-6, TNF-α, iNOS, COX-2, PGE2 and TXB2, generated by macrophages were suppressed when the cells were pretreated with harmine. Meanwhile, our findings showed that harmine administration effectively attenuated inflammation and apoptosis in H9c2 cells in the proinflammatory environment produced by macrophages, as evidenced by reductions in NLRP3 and cleaved caspase 3 levels and the p-NF-κB/NF-κB ratio. The western blot results indicated that the mechanisms underlying harmine-mediated inhibition of M1 polarization might be associated with suppression of STAT1/3, NF-κB and MAPK activation. Furthermore, an LPS injection induced cardiac dysfunction and decreased the survival rate of mice, which were alleviated by harmine treatment, and the relevant mechanism was possibly attributed to a drug-induced attenuation of the inflammatory and apoptotic processes in cardiomyocytes. Collectively, these results implied that harmine treatment protected against SIC by suppressing M1 phenotypic polarization and inflammation in macrophages.

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“…BLT1 was shown to be expressed on the surface of PMN, and pro-inflammatory macrophages (M1-macrophages). The authors observed that BLT1 inhibition was associated with amelioration of sepsis-induced myocardial injury [48]. GPR18 was shown to be expressed on PMN, monocytes, lymphocytes, M1-and anti-inflammatory (M2)macrophages.…”

Section: Spm Receptors On Immune Cells In Heart Tissuementioning

confidence: 98%

Resolution-promoting autacoids demonstrate promising cardioprotective effects against heart diseases

Hiram

2022

Mol Biol Rep

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Chronic heart diseases have in common an unresolved inflammatory status. In atherosclerosis, myocarditis, myocardial infarction, or atrial fibrillation, mounting evidence suggests that unresolved inflammation contributes to the chronicity, aggravation, and morbidity of the disease. Following cardiac injury or infection, acute inflammation is a normal and required process to repair damaged tissues or eliminate pathogens and promote restoration of normal functions and structures. However, if acute inflammation is not followed by resolution, a chronic and deleterious inflammatory status may occur, characterized by the persistence of inflammatory biomarkers, promoting aggravation of myocardial pathogenesis, abnormal structural remodeling, development of cardiac fibrosis, and loss of function. Although traditional antiinflammatory strategies, including the use of COX-inhibitors, to inhibit the production of inflammation promotors failed to promote homeostasis, mounting evidence suggests that activation of specific endogenous autacoids may promote resolution and perpetuate cardioprotective effects. The recent discovery of the active mechanism of resolution suggests that proresolving signals and cellular processes may help to terminate inflammation and combat the development of its chronic profile in cardiac diseases. This review discussed (I) the preclinical and clinical evidence of inflammation-resolution in cardiac disorders including atrial fibrillation; (II) how and why many traditional antiinflammatory treatments failed to prevent or cure cardiac inflammation and fibrosis; and (III) whether new therapeutic strategies may interact with the resolution machinery to have cardioprotective effects. Graphical abstract RvD D-series resolving, RvE E-series resolving, LXA4 lipoxin A4, MaR1 maresin-1

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Inhibition of 5-lipoxygenase is associated with downregulation of the leukotriene B4 receptor 1/ Interleukin-12p35 pathway and ameliorates sepsis-induced myocardial injury

Cited by 21 publications

References 44 publications

Expression Profile of Inflammation Response Genes and Potential Regulatory Mechanisms in Dilated Cardiomyopathy

Expression Profile of Inflammation Response Genes and Potential Regulatory Mechanisms in Dilated Cardiomyopathy

Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway

Resolution-promoting autacoids demonstrate promising cardioprotective effects against heart diseases

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