Mechanisms of Platelet-Activating Factor-induced Enhancement of VEGF Expression

Kim, Han-A; Seo, Kook Heon; Kang, Yeong-Rim; Ko, Hyun-Mi; Kim, Kyoung-Jin; Back, Hae-Kyong; Lee, Hern-Ku; Im, Suhn-Young

doi:10.1159/000325205

Cited by 15 publications

(5 citation statements)

References 41 publications

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“…We report that a PAF-R blockade significantly suppressed CNV-related molecules including VEGF, MCP-1, and IL-6. The suppression of VEGF and inflammation-related molecules associated with PAF-R blockage is consistent with the results of other studies that implicated PAF/PAF-R signaling in angiogenesis and inflammatory processes [53]–[55]. The molecular mechanisms functioning in CNV suppression by PAF-R blockage likely involve the inhibition of multiple inflammatory steps.…”

Section: Discussionsupporting

confidence: 90%

A Novel Platelet-Activating Factor Receptor Antagonist Inhibits Choroidal Neovascularization and Subretinal Fibrosis

et al. 2013

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Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration (AMD), the most common cause of blindness in developed countries. To date, the precise molecular and cellular mechanisms underlying CNV have not been elucidated. Platelet-activating factor (PAF) has been previously implicated in angiogenesis; however, the roles of PAF and its receptor (PAF-R) in CNV have not been addressed. The present study reveals several important findings concerning the relationship of the PAF-R signaling with CNV. PAF-R was detected in a mouse model of laser-induced CNV and was upregulated during CNV development. Experimental CNV was suppressed by administering WEB2086, a novel PAF-R antagonist. WEB2086-dependent suppression of CNV occurred via the inhibition of macrophage infiltration and the expression of proangiogenic (vascular endothelial growth factor) and proinflammatory molecules (monocyte chemotactic protein-1 and IL-6) in the retinal pigment epithelium–choroid complex. Additionally, WEB2086-induced PAF-R blockage suppresses experimentally induced subretinal fibrosis, which resembles the fibrotic subretinal scarring observed in neovascular AMD. As optimal treatment modalities for neovascular AMD would target the multiple mechanisms of AMD-associated vision loss, including neovascularization, inflammation and fibrosis, our results suggest PAF-R as an attractive molecular target in the treatment of AMD.

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Section: Discussionsupporting

confidence: 90%

A Novel Platelet-Activating Factor Receptor Antagonist Inhibits Choroidal Neovascularization and Subretinal Fibrosis

et al. 2013

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“…In our study, we demonstrated that resistin upregulated VEGF expression through the phosphorylation of Sp1 at Thr-453/Thr-739 (Figure 3), which is consistent with previous reports. It is reported that Egr-1 is also crucial in regulating VEGF expression [46], and there are also AP-2 and Egr-1 binding sites inside the multiple Sp1 binding sites within VEGF promoter. However, the specific DNA-protein binding bands could only be abolished by the competitive Sp1 consensus oligonucleotide, but not by AP-2 and Egr-1 consensus oligonucleotides (Figure 3E), indicating that Sp1 binding sites are critical for the resistin-induced VEGF gene expression in ovarian epithelial carcinoma.…”

Section: Resultsmentioning

confidence: 99%

Resistin Promotes the Expression of Vascular Endothelial Growth Factor in Ovary Carcinoma Cells

Pang

Zhang

et al. 2013

IJMS

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Resistin is a novel hormone that is secreted by human adipocytes and mononuclear cells and is associated with obesity, insulin resistance and inflammation. Recently, resistin has been postulated to play a role in angiogenesis. Here, we investigated the hypothesis that resistin regulates ovary carcinoma production of vascular endothelial growth factor (VEGF) and the angiogenic processes. We found that in human ovarian epithelial carcinoma cells (HO-8910), resistin (10–150 ng/mL) enhanced both VEGF protein and mRNA expression in a time- and concentration-dependent manner, as well as promoter activity. Furthermore, resistin enhanced DNA-binding activity of Sp1 with VEGF promoter in a PI3K/Akt-dependent manner. PI3K/Akt activated by resistin led to increasing interaction with Sp1, triggering a progressive phosphorylation of Sp1 on Thr453 and Thr739, resulting in the upregulation of VEGF expression. In an in vitro angiogenesis system for endothelial cells (EA.hy926) co-cultured with HO-8910 cells, we observed that the addition of resistin stimulated endothelial cell tube formation, which could be abolished by VEGF neutralizing antibody. Our findings suggest that the PI3K/Akt-Sp1 pathway is involved in resistin-induced VEGF expression in HO-8910 cells and indicates that antiangiogenesis therapy may be beneficial treatment against ovarian epithelial carcinoma, especially in obese patients.

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“…PAF also seems to induce the expression of VEGF via the downregulation of the tumor suppressor gene product, p53. 85 The beneficial effects attributed to the Mediterranean diet (rich in antioxidants) in reducing cancer incidence rests on its PAF inhibitory functions. 86,87 ►Fig.…”

Section: C-peroxisomesmentioning

confidence: 99%

Platelet–Cancer Interactions

Goubran

Stakiw

Radosevic

et al. 2014

Semin Thromb Hemost

115

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Platelets play a crucial role in the pathophysiological processes of hemostasis and thrombosis. Increasing evidence indicates that they fulfill much broader roles in balancing health and disease. The presence of tumor cells affects platelets both numerically, through a wide variety of mediators and cytokines, or functionally through tumor cell-induced platelet activation, the first step toward cancer-induced thrombosis. This induction results from signaling events through the different platelet receptors, or may be cytokine-mediated. Reciprocally, upon activation, the platelets will release a myriad of growth factors from their dense and α-granules and peroxisomes; these will directly impact tumor growth, tethering, and spread. A similar cross-talk is initiated between tumor microvesicles stimulating the platelets and platelet microparticles, promoting both thrombosis and tumor growth. A vicious loop of activation thereafter takes place. Platelets directly and indirectly promote tumor growth, and enable a molecular mimicry coating the malignant growth and allowing metastasizing cells to escape T-cell-mediated immunity and natural killer cell surveillance. Breaking this vicious activation loop with nonspecific platelet inhibitors, such as aspirin, or by targeting specific sites on the activation cascade may offer a mean to reduce both the risks of development and progression of cancer and the risk of thrombosis.

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Mechanisms of Platelet-Activating Factor-induced Enhancement of VEGF Expression

Cited by 15 publications

References 41 publications

A Novel Platelet-Activating Factor Receptor Antagonist Inhibits Choroidal Neovascularization and Subretinal Fibrosis

A Novel Platelet-Activating Factor Receptor Antagonist Inhibits Choroidal Neovascularization and Subretinal Fibrosis

Resistin Promotes the Expression of Vascular Endothelial Growth Factor in Ovary Carcinoma Cells

Platelet–Cancer Interactions

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