Soluble endoglin modulates the pro-inflammatory mediators NF-κB and IL-6 in cultured human endothelial cells

Varejckova, Michala; Gallardo-Vara, Eunate; Vicen, Matej; Vitverová, Barbora; Fikrová, Petra; Doleželová, Eva; Rathouska, Jana; Prašnická, Alena; Blazickova, Katerina; Mičuda, Stanislav; Bernabeu, Carmelo; Němečková, Ivana; Nachtigal, Petr

doi:10.1016/j.lfs.2017.03.014

Cited by 39 publications

(37 citation statements)

References 46 publications

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“…In fact, it has been reported that sEng contributes to endothelial dysfunction. Thus, sEng synergizes with hypercholesterolemia to aggravate endothelial and vessel wall dysfunction in vivo [43,45] and shows pro-inflammatory activity via nuclear factor-kappa B (NFkB) and interleukin 6 (IL6) in human endothelial cells in vitro [78]. Furthermore, exosomes from preeclamptic women induced vascular dysfunction by delivering sEng to endothelial cells [18].…”

Section: Discussionmentioning

confidence: 99%

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Gallardo-Vara

Gamella-Pozuelo

Pérez-Roque

et al. 2020

Cells

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Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators of hypertension, we analyzed the protein secretome of human endothelial cells in the presence of sEng. We found that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels, and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng + ) showed increased transcript levels of BMP4 in lungs, stomach, and duodenum, and increased circulating levels of BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng + mice, hypertension appeared 18 days after mating, coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 were positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng + mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the physiopathology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.

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Section: Discussionmentioning

confidence: 99%

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Gallardo-Vara

Gamella-Pozuelo

Pérez-Roque

et al. 2020

Cells

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“…Interestingly, Bacchiega et al found that the IL-6-blocking agent tocilizumab significantly reduced CRP concentrations, together with parameters of systemic inflammation [26]. IL-6 has many other functions, including activation of macrophages [27, 28] and stimulation of endothelial [29, 30] and vascular smooth muscle cells [31, 32]. Although IL-6 and miR-29b both have a number of clear effects on different stages in the formation of atherosclerosis and are, individually, important markers for CVD, we have shown that that the combination of miR-29b and IL-6 offers a better predictive marker for atherosclerosis than either miR-29b or IL-6 alone.…”

Section: Discussionmentioning

confidence: 99%

The Association of Circulating MiR-29b and Interleukin-6 with Subclinical Atherosclerosis

Huang

Chen

et al. 2017

Cell Physiol Biochem

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Background/Aims: Although it is widely acknowledged that atherosclerosis is mainly a chronic inflammatory process, in which both miR-29b and interleukin-6 (IL-6) play multifaceted roles, the association between miR-29b and IL-6 remains unknown. The aim of the present study was to explore the relationship between miR-29b and IL-6 and to test whether circulating levels of miR-29b and IL-6 could predict atherosclerosis. Methods: A total of 170 participants were divided into two groups according to carotid intima-media thickness (CIMT): study group (CIMT ≥ 0.9mm) and control group (CIMT < 0.9mm). Levels of circulating miR-29b and IL-6 were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The association of miR-29b and IL-6 levels with CIMT was assessed using Spearman correlation analysis and multiple linear regression analysis. Results: The study group showed higher miR-29b levels (31.61 ± 3.05 vs. 27.91 ± 1.71 Ct, p < 0.001) and IL-6 levels (3.40 ± 0.67 vs. 2.99 ± 0.37 pg/ml, p < 0.001), compared with the control group. CIMT was positively correlated with miR-29b (r = 0.587, p < 0.001) and IL-6 (r = 0.410, p < 0.001), and miR-29b levels were also correlated with IL-6 (r = 0.242, p = 0.001). Multiple linear regression analysis also showed that CIMT was positively correlated with miR-29b and IL-6. After adjustment for age, body mass index, systolic blood pressure, total cholesterol and C-reactive protein, CIMT was still closely correlated with miR-29b and IL-6. The combination of miR-29b and IL-6 (AUC = 0.901, p < 0.001) offered a better predictive index for atherosclerosis than either miR-29b (AUC = 0.867, p < 0.001) or IL-6 (AUC = 0.747, p < 0.001) alone. Conclusion: Circulating levels of miR-29b and IL-6 may be independently correlated with subclinical atherosclerosis, and may serve as novel biomarkers for the identification of atherosclerosis.

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“…eNOS expression increases in conditions of hypoxia mediated by the transcription factor HIF, as well as in experimental models of wound healing, post-ischemic states, and in the case of the rise of the vascular wall shear stress, where the transcription factor KLF2 is involved (Kruppel like factor). An increase in vascular pressure may result in a boost of eNOS expression with the involvement of NF-κB as well [38,[54][55][56]. The endothelial isoform is localized in caveo lae but is also found in the Golgi apparatus and the outer mitochondrial membrane [10,13,29,57].…”

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confidence: 99%

The biosynthesis of nitric oxide from L-arginine. Nitric oxide formation features and its functional role in mitochondria

Danylovych¹,

Bohach²,

Danylovych³

2018

Ukr.Biochem.J

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Modern data on biochemical patterns of nitric oxide biosynthesis in mammal cells from l-arginine in normoxic conditions is described. The attention of the authors is given to the results of the recent years on the structure and regulation features isoforms of No-synthase. The emphasis is put on the latest conception of the compartmentalization of certain isoforms of these enzymes in cells and on the possibility of the directed transport of nitric oxide in the vascular wall. The central place in the review is devoted to issues on the endogenous formation of NO in mitochondria and its potential physiological significance. Our own results on the identification of NO in mitochondria of the uterine smooth muscle, biochemical characteristics of this process and NO possible role in Са 2+ transport regulation by organelles are presented and discussed. K e y w o r d s: nitric oxide, mitochondria, No-synthases, cell compartments, calcium, smooth muscle. I n foreign scientific literature and, partly, in national periodicals, there are numerous review papers devoted to various aspects of the formation and biological activity of nitric oxide and its derivatives (nitric active forms). In view of this, in the presented article the authors tried to provide general ideas about the biosynthesis regularities and the role of NO in a cell in the most summarized version, primarily focusing on the problems that have become relevant in the last period of research, such as compartmentalization of certain isoforms of NO-synthase in cells and the possibility of directed transport of nitric oxide in the vascular wall. Particular attention is paid to the less highlighted and investigated problem -mitochondria own synthesis of nitric oxide and its possible functional activity in this compartment. Available material relates only to the synthesis of NO from L-arginine in the presence of O 2 and does not include important issues on reductase activity in hypoxic conditions and the functioning of the nitric oxide cycle in the mammalian organism. Numerous works by prof. Reutov V. P. and, for example, a review article in Ukrainian are devoted to these problems [1].Nitric oxide (NO) is a structurally simple low molecular amphiphilic free radical molecule. In biosystems NO has a relatively short time of existence (up to 5 sec depending on microenvironment) and can migrate at short distances from the generation sites what is determined by the rate of oxidation [2]. This limitation of diffusion implies the specificity of NO effect in individual cell compartments due to the colocalization of target proteins with NO sources in a multiprotein complex of signalosomes.Synthesis of NO in a cell is provided by the family of isoforms of NO-synthase (NOS), which, with the participation of NADPH as an electron source and the presence of O 2 , carry out a five-electron two-stage oxidation of the L-arginine guanidine group with the formation of NO and L-citrulline [2][3][4][5][6][7].NO is an almost universal messenger and regulatory molecule. NO signaling is carrie...

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Soluble endoglin modulates the pro-inflammatory mediators NF-κB and IL-6 in cultured human endothelial cells

Cited by 39 publications

References 46 publications

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

The Association of Circulating MiR-29b and Interleukin-6 with Subclinical Atherosclerosis

The biosynthesis of nitric oxide from L-arginine. Nitric oxide formation features and its functional role in mitochondria

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