The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

Bosmans, Laura A.; Bosch, Lena; Kusters, Pascal; Lutgens, Esther; Seijkens, Tom

doi:10.1007/s12265-020-09994-3

Cited by 44 publications

(30 citation statements)

References 72 publications

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“…CD154, a marker of cardiac ischemia and the ligand of CD40, was often elevated in septic patients (McLean et al, 2008). Both CD154 and CD40 are potential therapeutic targets of cardiovascular disease (Bosmans et al, 2020). In our study, XBJ and C0127s significantly reduced the expression of CD40.…”

Section: Xbj and C0127s Directly Or Indirectly Attenuate Cytokine Storm To Protect Cardiac Function And Improve Survival In Septic Shocksupporting

confidence: 54%

Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

Wang

Peng

et al. 2021

Front. Pharmacol.

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Sepsis-induced myocardial dysfunction is a major contributor to the poor outcomes of septic shock. As an add-on with conventional sepsis management for over 15 years, the effect of Xuebijing injection (XBJ) on the sepsis-induced myocardial dysfunction was not well understood. The material basis of Xuebijing injection (XBJ) in managing infections and infection-related complications remains to be defined. A murine cecal ligation and puncture (CLP) model and cardiomyocytes in vitro culture were adopted to study the influence of XBJ on infection-induced cardiac dysfunction. XBJ significantly improved the survival of septic-mice and rescued cardiac dysfunction in vivo. RNA-seq revealed XBJ attenuated the expression of proinflammatory cytokines and related signalings in the heart which was further confirmed on the mRNA and protein levels. Xuebijing also protected cardiomyocytes from LPS-induced mitochondrial calcium ion overload and reduced the LPS-induced ROS production in cardiomyocytes. The therapeutic effect of XBJ was mediated by the combination of paeoniflorin and hydroxysafflor yellow A (HSYA) (C0127-2). C0127-2 improved the survival of septic mice, protected their cardiac function and cardiomyocytes while balancing gene expression in cytokine-storm-related signalings, such as TNF-α and NF-κB. In summary, Paeoniflorin and HSYA are key active compounds in XBJ for managing sepsis, protecting cardiac function, and controlling inflammation in the cardiac tissue partially by limiting the production of IL-6, IL-1β, and CXCL2.

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Section: Xbj and C0127s Directly Or Indirectly Attenuate Cytokine Storm To Protect Cardiac Function And Improve Survival In Septic Shocksupporting

confidence: 54%

Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

Wang

Peng

et al. 2021

Front. Pharmacol.

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“…Another example is the CD40 gene. It is a member of the tumor necrosis factor receptor superfamily and encodes a protein playing a key role in a broad range of immune and inflammatory responses including T cell activation, immunoglobulin isotype switching and cytokine production [ 68 ]. CD40 has been implicated in various disorders, such as atherosclerosis, cardiovascular, metabolic (arterial hypertension, diabetes mellitus, etc.…”

Section: Discussionmentioning

confidence: 99%

“…CD40 has been implicated in various disorders, such as atherosclerosis, cardiovascular, metabolic (arterial hypertension, diabetes mellitus, etc. ), and the others [ 68 , 69 ]. Importantly, the CD40 DNA methylation levels [ 70 ] and CD40 expression (protein and mRNA) [ 71 ] were associated with gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Association of the functionally significant polymorphisms of the MMP9 gene with H. pylori-positive gastric ulcer in the Caucasian population of Central Russia

et al. 2021

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Background and purpose The study analyzed the association of functionally significant polymorphisms of matrix metalloproteinases (MMPs) genes with the development of gastric ulcer (GU) in Caucasians from Central Russia. Methods The 781 participants, including 434 patients with GU (196 Helicobacter pylori (H. pylori)-positive and 238 H. pylori-negative) and 347 controls (all H. pylori-negative) were recruited for the study. Ten SNPs of the MMP1 (rs1799750), MMP2 (rs243865), MMP3 (rs679620), MMP8 (rs1940475), and MMP9 (rs3918242, rs3918249, rs3787268, rs17576, rs17577, and rs2250889) genes were considered for association with GU using multiple logistic regression. The SNPs associated with GU and loci linked (r2≥0.8) to them were analyzed in silico for their functional assignments. Results The SNPs of the MMP9 gene were associated with H. pylori-positive GU: alleles C of rs3918249 (OR = 2.02, pperm = 0.008) and A of rs3787268 (OR = 1.60–1.82, pperm ≤ 0.016), and eight haplotypes of all studied MMP9 gene SNPs (OR = 1.85–2.04, pperm ≤ 0.016) increased risk for H. pylori-positive GU. None of the analyzed SNPs was independently associated with GU and H. pylori-negative GU. Two haplotypes of the MMP9 gene (contributed by rs3918242, rs3918249, rs17576, and rs3787268) increased risk for GU (OR = 1.62–1.65, pperm ≤ 0.006). Six loci of the MMP9 gene, which are associated with H. pylori-positive GU, and 65 SNPs linked to them manifest significant epigenetic effects, have pronounced eQTL (17 genes) and sQTL (6 genes) values. Conclusion SNPs of the MMP9 were associated with H. pylori-positive GU but not with H. pylori-negative GU in Caucasians of Central Russia.

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“…It enhances leukocyte recruitment to the sites of vascular inflammation. In advanced lesions, it stimulates macrophages to increase production of matrix metalloproteinases (MMP) [ 7 ], particularly MMP-9, which is responsible for plaque destabilization and rupture [ 8 ]. Monocyte chemoattractant protein -1 (MCP-1) is another protein that promotes plaque vulnerability.…”

Section: Introductionmentioning

confidence: 99%

Elevation of CD40/CD40L Inflammatory Pathway Molecules in Carotid Plaques from Moderate-and-Severe Obstructive Sleep Apnea Patients

et al. 2021

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A chronic inflammatory process characteristic of obstructive sleep apnea promotes vascular endothelial dysfunction and atherogenesis. This process can lead to destabilization and rupture of cardiovascular plaques, which clinically manifests as an acute coronary syndrome or stroke. The aim of this study was to investigate the inflammatory pathway leading to plaque destabilization in non-to-mild and moderate-to-severe groups of OSA patients. This prospective study involved enrollment of patients scheduled for endarterectomy. A sleep study was performed prior to surgery. Immunohistochemistry was performed on atherosclerotic plaques from carotid arteries obtained during standard open endarterectomy to determine levels of CD40, CD40L receptors, MCP-1, and MMP-9. The 46 patients included 14 controls, 13 with mild, 11 with moderate, and 8 with severe OSA. Increased expression of CD40, CD40L receptors, MCP-1, and MMP-9 were found to be proportionate with OSA severity. However, significant differences among groups were observed only for MCP-1 (p = 0.014). Increased expression of inflammatory markers (CD40, CD40L, MCP-1, MMP-9) is associated with increasing OSA severity. This suggests the CD40-CD4-L inflammatory pathway may contribute to plaque instability and rupture in OSA patients.

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The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

Cited by 44 publications

References 72 publications

Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

Association of the functionally significant polymorphisms of the MMP9 gene with H. pylori-positive gastric ulcer in the Caucasian population of Central Russia

Elevation of CD40/CD40L Inflammatory Pathway Molecules in Carotid Plaques from Moderate-and-Severe Obstructive Sleep Apnea Patients

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