Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm

Camacho, Mercedes; Dilmé, Jaume; Solà-Villà, D.; Rodrı́guez, Cristina; Bellmunt, Sergi; Siguero, Laura; Alcolea, Sonia; Romero, J.-M.; Escudero, José Román; Martínez-González, José; Vilá, Luis M.

doi:10.1194/jlr.m042481

Cited by 37 publications

(63 citation statements)

References 39 publications

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“…This was also supported by the action of the more specific EP‐4 antagonist CJ42794, which significantly inhibited cPGI 2 ‐induced in vitro angiogenesis. We have previously reported that PGE 2 ‐induced in vitro angiogenesis was mainly dependent on the EP‐4 receptor in ECs . Our results do not rule out the possibility that other prostanoid receptors could also be involved and we have no direct evidence of PGI 2 binding to EP‐4.…”

Section: Discussioncontrasting

confidence: 84%

“…None of these antagonists modified the effect of cPGI 2 on in vitro angiogenesis (Figure B), indicating that neither IP nor PPARδ mediated the effect of cPGI 2 in HUVEC tube formation. We have previously reported that PGE 2 ‐induced angiogenesis in vitro was mainly dependent on the EP‐4 receptor in ECs . Other authors have also reported that PGI 2 produces biological activities through EP‐4 activation .…”

Section: Resultsmentioning

confidence: 83%

“…Tissue specimens of all patients included in the study were immediately stabilized by inclusion in RNAlater (Qiagen GmbH, Hilden, Germany) after biopsy and stored at −80 °C until processing. Total RNA was extracted and RT‐PCR performed as described previously . Relative expression was expressed as transcript/β‐actin ratios.…”

Section: Methodsmentioning

confidence: 99%

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Prostacyclin‐synthase expression in head and neck carcinoma patients and its prognostic value in the response to radiotherapy

Camacho

Piñeiro

Alcolea

et al. 2014

The Journal of Pathology

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Prostacyclin (PGI2 ) plays a role in cancer progression but the mechanism is currently poorly understood. Additionally, no data are available about the prognostic value of the PGI2 pathway in head and neck squamous cell carcinoma (HNSCC) therapy. We evaluated the expression of the PGI2 pathway in HNSCC patients. PGI2 production and PGI synthase (PGIS) expression, in terms of mRNA (RT-PCR) and protein (immunoblotting), were lower in tumour samples than in non-tumoural mucosa, whereas, as expected, COX-2 expression was increased in HNSCC tumour samples. Using local control of the tumour after radiotherapy or chemoradiotherapy as a dependent variable, patients were classified into two categories of PGIS transcript levels. The high-PGIS group had a significantly lower frequency of local and distant failure than the low-PGIS group, and the 5-year cancer-specific survival was higher [90.2% (95% CI 81.0-99.4%) versus 60.5% (95% CI 44.4-76.6%)]. None of the four HNSCC cell lines analysed expressed PGIS and therefore they did not produce PGI2 . However, HNSCC-conditioned media enhanced PGI2 production in endothelial cells (ECs). The stable analogue of PGI2 , carbaprostacyclin (cPGI2 ), exerted little effect on HNSCC cell line migration, and no effect on cell cycle distribution or proliferation rate after radiation injury was observed. Nevertheless, cPGI2 promoted EP-4-dependent in vitro angiogenesis. Von Willebrand factor expression (EC marker) and capillary density were significantly higher in the group of patients with high expression of PGIS. Our results indicate that PGIS expression was associated with radiotherapy efficiency. Although we do not provide direct evidence of a relationship between tumour vascularization and radiotherapy efficiency, our results suggest that the effect of PGI2 is related to its ability to promote vascularization. These results also support the concept that co-adjuvant therapy with PGIS enhancers, such as retinoids, could have therapeutic value for HNSCC treatment.

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Section: Discussioncontrasting

confidence: 84%

Section: Resultsmentioning

confidence: 83%

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Prostacyclin‐synthase expression in head and neck carcinoma patients and its prognostic value in the response to radiotherapy

Camacho

Piñeiro

Alcolea

et al. 2014

The Journal of Pathology

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“…It has been reported that COX‐2 activity and expression maybe play a primary role in the formation and expansion of AAA . Compared to health donors, COX‐2 expression is obviously increased in AAA patients . On the contrary, the inhibition of COX‐2 depressed the increased vasoconstrictor response and endothelial dysfunction induced by Ang II infusion .…”

Section: Discussionmentioning

confidence: 98%

Regulatory T cells protected against abdominal aortic aneurysm by suppression of the COX‐2 expression

Liu

Kong

et al. 2019

J Cellular Molecular Medi

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CD4+CD25+ regulatory T cells (Tregs) have been shown to protect against the development of abdominal aortic aneurysm (AAA). Cyclooxygenase‐2 (COX‐2), a pro‐inflammatory protein, can convert arachidonic acid into prostaglandins (PGs). The present study was aimed to investigate the effect of Tregs on COX‐2 expression in angiotension II (Ang II)‐induced AAA in ApoE−/− mice. Tregs were injected via tail vein in every 2 weeks. Ang II was continuously infused by a micropump for 28 days to induce AAA. In vivo, compared with the control group, adoptive transfer of Tregs significantly reduced the incidence of AAA, maximal diameter, and the mRNA and protein expression of COX‐2 in mice. Immunofluorescence showed that Tregs treatment reduced COX‐2 expression both in smooth muscle cells (SMCs) and macrophages in AAA. In vitro, the Western blot analysis showed that Tregs reduced Ang II‐induced COX‐2 expression in macrophages and SMCs. Meanwhile, ELISA showed that Tregs reduced Ang II‐induced prostaglandin E2 (PGE2) secretion. Moreover, Tregs increased SMC viability and induced transition of macrophages phenotype from M1 to M2. In conclusion, Tregs treatment dramatically decreased the expression of COX‐2 in vivo and in vitro, suggesting that Tregs could protect against AAA through inhibition of COX‐2. The study may shed light on the immune treatment of AAA.

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“…Prostaglandin E 2 (PGE 2 ) is associated with human cardiovascular 1, 2 and cerebrovascular disease 3 . PGE 2 also is involved in the pathogenesis of several animal models of cardiovascular 4–6 and cerebrovascular disease 7, 8 .…”

Section: Introductionmentioning

confidence: 99%

Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice

Silva

Mitchell²,

Kung

et al. 2015

Neurosurgery

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Background Inflammation plays an important role in formation and rupture of intracranial aneurysms. Expression of microsomal prostaglandin E2 (PGE2) synthase type 1 (mPGES-1) is increased in the wall of intracranial aneurysms in humans. PGE2, a by-product of mPGES-1, is associated with inflammation and cerebrovascular dysfunction. Objective To test the hypothesis that deletion of mPGES-1 decreases the formation and rupture of intracranial aneurysms in a murine model. Methods Intracranial aneurysms were induced in wild type (WT) and mPGES-1 deficient (mPGES-1 KO) mice using a combination of deoxycorticosterone acetate (DOCA)-salt-induced hypertension and intracranial injection of elastase in the basal cistern. Prevalence of aneurysms, subarachnoid hemorrhage (SAH), and mortality were assessed. We also tested effects of administration of aspirin (6mg/kg/d) by gavage and PGE2 (1mg/kg/d) by subcutaneous infusion. Results Systolic blood pressure (SBP) and prevalence of aneurysm were similar in WT and mPGES-1 KO mice. However, mortality and prevalence of SAH were markedly increased in mPGES-1 KO mice (p <0.05). Bone marrow reconstitution studies suggest that mPGES-1 derived from leukocytes does not appear to increase rupture of intracranial aneurysms. Aspirin, but not PGE2, attenuated the increased mortality in mPGES-1 KO mice (p <0.05). Conclusion Vascular mPGES-1 plays a protective role in blood vessels and attenuates rupture of cerebral aneurysms. In contrast to effects on abdominal aneurysms, mPGES-1 deficiency is associated with an increase in rupture of cerebral aneurysms and mortality, which are attenuated by low-dose aspirin.

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Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm

Cited by 37 publications

References 39 publications

Prostacyclin‐synthase expression in head and neck carcinoma patients and its prognostic value in the response to radiotherapy

Prostacyclin‐synthase expression in head and neck carcinoma patients and its prognostic value in the response to radiotherapy

Regulatory T cells protected against abdominal aortic aneurysm by suppression of the COX‐2 expression

Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice

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