C‐reactive protein promotes platelet adhesion to endothelial cells: a potential pathway in atherothrombosis

Yaron, Gil; Brill, Alexander; Dashevsky, Olga; Yosef-Levi, Irit Mor; Grad, Etty; Danenberg, Haim; Varon, David

doi:10.1111/j.1365-2141.2006.06198.x

Cited by 47 publications

(43 citation statements)

References 35 publications

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“…CRP has been reported as a potent peptide that causes platelet adhesion to epithelial cells, thereby regulating atherothrombosis (39). This step is also regulated by vitronectin and its receptor, since they interact with thrombin and antithrombin III (40).…”

Section: Discussionmentioning

confidence: 99%

Functional connections and pathways of coenzyme Q10‐inducible genes: An in‐silico study

et al. 2007

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Coenzyme Q10 (CoQ10, ubiquinone) is an essential cofactor in the electron transport chain, serves as a potent antioxidant in mitochondria and lipid membranes, and is often used as a dietary supplement for a number of diseases including cardiovascular diseases. Recently, we obtained evidence that CoQ10 (Kaneka Q10™) affects the expression of hundreds of human genes. To decipher the functional and regulatory connections of these genes, a literature search combined with transcription factor binding site analysis was performed using Genomatix BiblioSphere and MatInspector. This in‐silico analysis revealed 17 CoQ10‐inducible genes which are functionally connected by signalling pathways of G‐protein coupled receptors, JAK/STAT, integrin, and beta‐arrestin. Promoter analysis of these CoQ10‐inducible genes showed one group of NFκ B‐regulated genes, namely IL5, thrombin, vitronectin receptor and C‐reactive protein (CRP). Furthermore, a common promoter framework containing binding sites of the transcription factor families EVI1, HOXF, HOXC, and CLOX was identified in the promoters of IL5, CRP, and vitronectin receptor. The identified CoQ10‐inducible genes and pathways play an important role in inflammatory response. Since these effects are based on an in‐vitro study, the effect of CoQ10 on vascular health in vivo needs to be addressed in further animal and/or human intervention studies. IUBMB Life, 59: 628‐633, 2007

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Section: Discussionmentioning

confidence: 99%

Functional connections and pathways of coenzyme Q10‐inducible genes: An in‐silico study

et al. 2007

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“…We have previously demonstrated that PKC activation and PKC-dependent MAPK activation are major participants in the regulation of macrophage LPL (19,20,22,23). Although indirect evidence has been provided for a role of PKC in CRP-induced platelet adhesion and VCAM-1 expression (41,42), the levels of PKC activity in CRP-treated vascular cells has not yet been documented. In the present study, we demonstrated that CRP increases the expression of conventional PKC isoforms in macrophages.…”

Section: Discussionmentioning

confidence: 99%

C-reactive protein enhances macrophage lipoprotein lipase expression

Maingrette

Renier

2008

Journal of Lipid Research

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High serum levels of C-reactive protein (CRP), a strong predictor of cardiovascular events, are documented in patients with type 2 diabetes. Accumulating evidence suggests that CRP could directly promote arterial damage. To determine the role of CRP in diabetic atherosclerosis, we examined the effect of CRP on the expression of macrophage lipoprotein lipase (LPL), a proatherogenic molecule upregulated in type 2 diabetes. Treatment of human macrophages with native CRP increased, in a dose-and timedependent manner, LPL protein expression and secretion. Modified CRP reproduced these effects. Preincubation of human macrophages with antioxidants, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) inhibitors prevented CRP-induced LPL expression. Exposure of human macrophages to CRP further increased intracellular reactive oxygen species generation, classic PKC isozymes expression, and extracellular signal-regulated protein kinase 1/2 phosphorylation. In CRP-treated J774 macrophages, increased macrophage LPL mRNA levels and enhanced binding of nuclear proteins to the activated protein-1 (AP-1)-enhancing element were observed. These effects were prevented by antioxidants, as well as by PKC, MAPK, and AP-1 inhibitors. These data show for the first time that CRP directly increases macrophage LPL expression and secretion. Given the predominant role of macrophage LPL in atherogenesis, LPL might represent a novel factor underlying the adverse effect of CRP on the diabetic vasculature.-Maingrette, F., L. Li, and G. Renier. C-reactive protein enhances macrophage lipoprotein lipase expression. J. Lipid Res. 2008Res. . 49: 1926Res. -1935 Since the hypothesis that inflammation might be an accomplice in the pathogenesis of atherosclerosis and type 2 diabetes was first proposed, many epidemiological and clinical studies have shown that circulating markers of inflammation predict the risk of future cardiovascular (CV) events and type 2 diabetes and that an ongoing acute phase response is present in patients with type 2 diabetes (1). In addition to being a CV risk marker (2, 3), C-reactive protein (CRP) could also make a direct contribution to the atherosclerotic process. Supporting this possibility, it has been shown that CRP is present in the plaque (4) and that exposure of cultured vascular cells to CRP leads to various proinflammatory and proatherogenic effects. Among the cell types found in the lesion, monocytes/macrophages have essential functions in all phases of atherosclerosis. Interaction of CRP with these cells induces an increase in the secretion of inflammatory mediators such as cytokines and chemokines (5, 6). Additional effects of CRP on monocytes/macrophages include induction of colony stimulating factor (CSF), matrix metalloproteinase (MMP), nitric oxide, and tumoricidal activity (7-10). Most importantly, CRP also appears to promote infiltration of monocytes into the vessel wall (11) and their subsequent development into foam cells (12).Lipoprotein lipase (LPL) is a key enzyme in the hydro...

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“…Platelet adhesion to MHECs from CRPtg or wild-type mice and to human umbilical vein endothelial cells (HUVECs) was studied using the CPA, as previously described (39). Forty thousand MHECs or HUVECs at passage 2 to 3 were plated on four-well plates.…”

Section: Methodsmentioning

confidence: 99%

Endothelial C-reactive protein increases platelet adhesion under flow conditions

Grad

Pachino

Danenberg

2011

American Journal of Physiology-Heart and Circulatory Physiology

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While data regarding the pathogenetic role of C-reactive protein (CRP) in atherothrombosis are accumulating, it is still controversial whether local CRP secretion is of any pathobiological significance. The present study examined whether endothelial-derived CRP modulates autocrine prothrombotic activity. Endothelial cells were isolated from hearts of mice transgenic to human CRP and grown in primary cultures. Human CRP expression was confirmed in these cells compared with no expression in cultures derived from wild-type congenes. Adhesion of human platelets to endothelial cells was studied in the “cone and plate” flow system. Platelet adhesion to cells expressing CRP was significantly increased compared with that in controls ( n = 6, P < 0.01). The proadhesive effect of CRP was significantly suppressed in mouse heart endothelial cells and in human umbilical vein endothelial cells following treatment with small interfering RNA for human CRP. Adhesion was modulated by an increase in P-selectin. P-selectin expression correlated with a proadhesive phenotype, and blocking P-selectin with neutralizing antibody significantly decreased the adhesion of platelets to CRP-expressing cells (40.4 ± 10.5 to 9.4 ± 6.9 platelets/high-power field, n = 5 to 6, P < 0.01). In conclusion, human CRP that is locally produced in endothelial cells increases platelet adhesion to endothelial cells under normal shear flow conditions. These findings indicate that CRP exerts a local effect on endothelial cells via P-selectin expression, which promotes platelet adhesion and subsequent thrombus formation.

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C‐reactive protein promotes platelet adhesion to endothelial cells: a potential pathway in atherothrombosis

Cited by 47 publications

References 35 publications

Functional connections and pathways of coenzyme Q10‐inducible genes: An in‐silico study

Functional connections and pathways of coenzyme Q10‐inducible genes: An in‐silico study

C-reactive protein enhances macrophage lipoprotein lipase expression

Endothelial C-reactive protein increases platelet adhesion under flow conditions

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