Inflammatory Mechanisms Contributing to Endothelial Dysfunction

Theofilis, Panagiotis; Sagris, Μarios; Oikonomou, Evangelos; Antonopoulos, Alexios S; Siasos, Gerasimos; Tsioufis, Costas; Tousoulis, Dimitris

doi:10.3390/biomedicines9070781

Cited by 266 publications

(216 citation statements)

References 213 publications

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“…In addition to targeting HMGB1, a key driver of inflammatory and immune responses in numerous disease settings [ 86 – 89 ], miR-126 can target multiple other disease-associated genes of relevance to this study, including angiogenesis-related vascular endothelial growth factor A, sprouty-related protein-1, phosphoinositidol-3 kinase regulatory subunit-2 1, and the adapter molecule crk [ 90 – 92 ]. Our discovery that acidosis exerts marked control over HMBG1 and Bcl2 expression as well as downstream inflammation responders and Akt, via miR-126 and HIF-1 α (summarized in Figure 6 ), in the context of chronic ischemia is novel and represents important additions to our understanding of vascular inflammation and cell survival during ischemic disease, including atherosclerosis and vasculatures of solid tumors, wherein hypoxia and acidosis are integral disease components.…”

Section: Discussionmentioning

confidence: 99%

MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis

Liu

Wei²,

Wei

et al. 2021

Disease Markers

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Crosstalk between molecular regulators miR-126, hypoxia-inducible factor 1-alpha (HIF-1-α), and high-mobility group box-1 (HMGB1) contributes to the regulation of inflammation and angiogenesis in multiple physiological and pathophysiological settings. Here, we present evidence of an overriding role for miR-126 in the regulation of HMGB1 and its downstream proinflammatory effectors in endothelial cells subjected to hypoxia with concurrent acidosis (H/A). Methods. Primary mouse endothelial cells (PMEC) were exposed to hypoxia or H/A to simulate short or chronic low-flow ischemia, respectively. RT-qPCR quantified mRNA transcripts, and proteins were measured by western blot. ROS were quantified by fluorogenic ELISA and luciferase reporter assays employed to confirm an active miR-126 target in the HMGB1 3 ′ UTR. Results. Enhanced expression of miR-126 in PMECs cultured under neutral hypoxia was suppressed under H/A, whereas the HMGB1 expression increased sequentially under both conditions. Enhanced expression of HMGB1 and downstream inflammation markers was blocked by the premiR-126 overexpression and optimized by antagomiR. Compared with neutral hypoxia, H/A suppressed the HIF-1α expression independently of miR-126. The results show that HMGB1 and downstream effectors are optimally induced by H/A relative to neutral hypoxia via crosstalk between hypoxia signaling, miR-126, and HIF-1α, whereas B-cell lymphoma 2(Bcl2), a HIF-1α, and miR-126 regulated gene expressed optimally under neutral hypoxia. Conclusion. Inflammatory responses of ECs to H/A are dynamically regulated by the combined actions of hypoxia, miR-126, and HIF-1α on the master regulator HMGB1. The findings may be relevant to vascular diseases including atherosclerotic occlusion and interiors of plaque where coexisting hypoxia and acidosis promote inflammation as a defining etiology.

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Section: Discussionmentioning

confidence: 99%

MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis

Liu

Wei²,

Wei

et al. 2021

Disease Markers

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“…The pathophysiological role of selectins, particularly P-Selectin and E-selectin, in atherosclerotic cardiovascular disease is supported both by experimental and human studies [7]. In particular, epidemiological studies have reported significant and positive associations between the concentration of soluble selectins and adverse cardiovascular outcomes.…”

Section: Introductionmentioning

confidence: 97%

“…Therefore, the available evidence suggests that soluble selectins play a critical role in the pathophysiology of atherosclerosis and endothelial dysfunction and as markers of cardiovascular risk [7], and that interventions targeting this family of cell adhesion molecules might exert atheroprotective effects [13].…”

Section: Introductionmentioning

confidence: 99%

Systematic Review and Meta-Analysis of the Effect of Statins on Circulating E-Selectin, L-Selectin, and P-Selectin

Zinellu

Mangoni

2021

Biomedicines

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The pleiotropic effects of statins might involve preventing inflammatory cell adhesion to the endothelium, which is a critical step in the pathogenesis of atherosclerosis. We conducted a systematic review and meta-analysis of the effects of statins on the circulating cell adhesion molecules E-Selectin, L-Selectin, and P-Selectin. A literature search was conducted in PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 61 studies, statins significantly reduced P-selectin (standard mean difference, SMD = −0.39, 95% CI −0.55 to −0.22, p < 0.001; moderate certainty of evidence), L-selectin (SMD = −0.49, 95% CI −0.89 to −0.10, p = 0.014; very low certainty of evidence), and E-Selectin (SMD = −0.73, 95% CI −1.02 to −0.43, p < 0.001; moderate certainty of evidence), independently of baseline lipid profile and other study and patient characteristics. The corresponding pooled SMD values in sensitivity analysis were not substantially altered when individual studies were sequentially removed. Simvastatin had a significant lowering effect on both P-selectin and E-selectin. Therefore, statins significantly reduce circulating selectins. Further studies are required to investigate whether selectin lowering mediates cardiovascular risk reduction with these agents. (PROSPERO registration number: CRD42021282778).

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“…The expression of adhesion molecules in endothelial cells is crucial for the effective adhesion of leukocytes, such as blood monocytes, to the endothelium and subsequent infiltration to the site of infection [28,29]. Thus, Icam-1, Vcam-1, E-selectin, and P-selectin represent key factors in endothelial inflammation and monocyte recruitment [29,30]. We therefore studied the expression of adhesion molecules in endothelial cells upon LPS stimulation, observing a strong and persistent increase (~10-20 fold) for Icam-1, Vcam-1, and E-selectin.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of C1q/Tumor Necrosis Factor-Related Protein 3 (CTRP3) in Endothelial Cells

Schmid

Vlacil

Schuett

et al. 2021

Cells

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The C1q/TNF-related protein 3 (CTRP3) represents a pleiotropic adipokine reciprocally associated with obesity and type 2 diabetes mellitus and exhibits anti-inflammatory properties in relation to lipopolysaccharides (LPS)-mediated effects in adipocytes, as well as monocytes/macrophages. Here, we focused on the influence of CTRP3 on LPS-mediated effects in endothelial cells in order to expand the understanding of a possible anti-inflammatory function of CTRP3 in a setting of endotoxemia. An organ- and tissue-specific expression analysis by real-time PCR revealed a considerable Ctrp3 expression in various adipose tissue compartments; however, higher levels were detected in the aorta and in abundantly perfused tissues (bone marrow and the thyroid gland). We observed a robust Ctrp3 expression in primary endothelial cells and a transient upregulation in murine endothelial (MyEND) cells by LPS (50 ng/mL). In MyEND cells, CTRP3 inhibited the LPS-induced expression of interleukin (Il)-6 and the tumor necrosis factor (Tnf)-α, and suppressed the LPS-dependent expression of the major endothelial adhesion molecules Vcam-1 and Icam-1. The LPS-induced adhesion of monocytic cells to an endothelial monolayer was antagonized by CTRP3. In C57BL/6J mice with an LPS-induced systemic inflammation, exogenous CTRP3 did not affect circulating levels of TNF-α, ICAM-1, and VCAM-1. In conclusion, we characterized CTRP3 beyond its function as an adipokine in a setting of vascular inflammation. CTRP3 inhibited LPS-induced endothelial expression of adhesion molecules and monocyte cell adhesion, indicating an important vascular anti-inflammatory role for CTRP3 in endotoxemia.

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Inflammatory Mechanisms Contributing to Endothelial Dysfunction

Cited by 266 publications

References 213 publications

MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis

MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis

Systematic Review and Meta-Analysis of the Effect of Statins on Circulating E-Selectin, L-Selectin, and P-Selectin

Anti-Inflammatory Effects of C1q/Tumor Necrosis Factor-Related Protein 3 (CTRP3) in Endothelial Cells

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