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Conference Paper: Co-activation of PKCdelta/ERK1/2 and P38 MAPK mediates angiotensin II-induced cyclooxygenase-2 up-regulation in endothelial cells and the clinical implications

TitleCo-activation of PKCdelta/ERK1/2 and P38 MAPK mediates angiotensin II-induced cyclooxygenase-2 up-regulation in endothelial cells and the clinical implications
Authors
KeywordsPharmacy and pharmacology environmental studies
Toxicology and environmental safety
Issue Date2010
PublisherBlackwell Publishing Ltd. The Journal's web site is located at http://www.blackwellpublishing.com/journals/PTO
Citation
The 16th World Congress on Basic and Clinical Pharmacology (WorldPharma2010), Copenhagen, Denmark, 17-23 July 2010. In Basic & Clinical Pharmacology & Toxicology, 2010, v. 107, suppl. 1, p. 149 How to Cite?
AbstractElevated angiotensin II (AngII) levels have been implicated in patients with hypertension and diabetic vascular complications, while cyclooxy-genase-2 (COX-2) is regarded as a culprit of vascular inflammation. However, it remains elusive whether COX-2 acts directly as a downstream effector in mediating AngII-induced vascular pathogenesis. The present study aimed to investigate this relationship and the intracellular signalling cascades linking these two factors. Primary endothelial cells were freshly cultivated from rat thoracic aortas. The COX-2 expression was minimal in untreated endothelial cells but reached a maximum after 8-hour incubation with 100 nM AngII. Losartan and RNA synthesis inhibitor (actinomycin-D) inhibited COX-2 over-expression. Of known transcriptional pathways examined, only inhibitors of p38 MAPK and ERK1/2 (SB-202190 and PD-98059) decreased COX-2 expression, and co-treatment caused additive effect, suggesting a joint mediation through both kinases. PKC inhibitor (GF109203X), and particularly, the specific PKCδ inhibitor (rottlerin), prevented AngII-induced phosphorylation of ERK1/2 and COX-2 expression, suggesting an upstream regulation of ERK1/2 by PKCδ. Pivotal role of PKC in AngII-induced COX-2 expression was further supported by a similar stimulatory effect of PKC activator, signified by the translocation of PKCδ to the membrane and confirmed by its phosphorylation (Tyr311). Aortae of AngII-infused rats and renal arteries from patients with hypertension and diabetes exhibited an increased endothelial COX-2 expression. The present novel findings indicate that activation of p38 MAPK and PKCδ/ERK1/2 is critical in AngII-mediated COX-2 up-regulation. This study provides an important molecular basis for further elucidation on how the COX-2-derived products participate in vascular inflammation in hypertension and diabetes.
DescriptionFocused Conference Group: FC15 – Endotheliumin Health and Disease. Paper No. 1595
Persistent Identifierhttp://hdl.handle.net/10722/129898
ISSN
2015 Impact Factor: 3.097
2015 SCImago Journal Rankings: 0.539

 

DC FieldValueLanguage
dc.contributor.authorWong, SLen_US
dc.contributor.authorLau, CWen_US
dc.contributor.authorWong, WTen_US
dc.contributor.authorXu, Aen_US
dc.contributor.authorAu, CLen_US
dc.contributor.authorYao, Xen_US
dc.contributor.authorHuang, Yen_US
dc.date.accessioned2010-12-23T08:44:00Z-
dc.date.available2010-12-23T08:44:00Z-
dc.date.issued2010en_US
dc.identifier.citationThe 16th World Congress on Basic and Clinical Pharmacology (WorldPharma2010), Copenhagen, Denmark, 17-23 July 2010. In Basic & Clinical Pharmacology & Toxicology, 2010, v. 107, suppl. 1, p. 149en_US
dc.identifier.issn1742-7835-
dc.identifier.urihttp://hdl.handle.net/10722/129898-
dc.descriptionFocused Conference Group: FC15 – Endotheliumin Health and Disease. Paper No. 1595-
dc.description.abstractElevated angiotensin II (AngII) levels have been implicated in patients with hypertension and diabetic vascular complications, while cyclooxy-genase-2 (COX-2) is regarded as a culprit of vascular inflammation. However, it remains elusive whether COX-2 acts directly as a downstream effector in mediating AngII-induced vascular pathogenesis. The present study aimed to investigate this relationship and the intracellular signalling cascades linking these two factors. Primary endothelial cells were freshly cultivated from rat thoracic aortas. The COX-2 expression was minimal in untreated endothelial cells but reached a maximum after 8-hour incubation with 100 nM AngII. Losartan and RNA synthesis inhibitor (actinomycin-D) inhibited COX-2 over-expression. Of known transcriptional pathways examined, only inhibitors of p38 MAPK and ERK1/2 (SB-202190 and PD-98059) decreased COX-2 expression, and co-treatment caused additive effect, suggesting a joint mediation through both kinases. PKC inhibitor (GF109203X), and particularly, the specific PKCδ inhibitor (rottlerin), prevented AngII-induced phosphorylation of ERK1/2 and COX-2 expression, suggesting an upstream regulation of ERK1/2 by PKCδ. Pivotal role of PKC in AngII-induced COX-2 expression was further supported by a similar stimulatory effect of PKC activator, signified by the translocation of PKCδ to the membrane and confirmed by its phosphorylation (Tyr311). Aortae of AngII-infused rats and renal arteries from patients with hypertension and diabetes exhibited an increased endothelial COX-2 expression. The present novel findings indicate that activation of p38 MAPK and PKCδ/ERK1/2 is critical in AngII-mediated COX-2 up-regulation. This study provides an important molecular basis for further elucidation on how the COX-2-derived products participate in vascular inflammation in hypertension and diabetes.-
dc.languageengen_US
dc.publisherBlackwell Publishing Ltd. The Journal's web site is located at http://www.blackwellpublishing.com/journals/PTO-
dc.relation.ispartofBasic & Clinical Pharmacology & Toxicologyen_US
dc.rightsThe definitive version is available at www.blackwell-synergy.com-
dc.subjectPharmacy and pharmacology environmental studies-
dc.subjectToxicology and environmental safety-
dc.titleCo-activation of PKCdelta/ERK1/2 and P38 MAPK mediates angiotensin II-induced cyclooxygenase-2 up-regulation in endothelial cells and the clinical implicationsen_US
dc.typeConference_Paperen_US
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1742-7835&volume=107, suppl. 1&spage=149&epage=&date=2010&atitle=Co-activation+of+PKCdelta/ERK1/2+and+P38+MAPK+mediates+angiotensin+II-induced+cyclooxygenase-2+up-regulation+in+endothelial+cells+and+the+clinical+implications-
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_US
dc.identifier.hkuros176615en_US
dc.identifier.volume107, suppl. 1-
dc.identifier.spage149en_US
dc.identifier.epage149-
dc.description.otherThe 16th World Congress on Basic and Clinical Pharmacology (WorldPharma2010), Copenhagen, Denmark, 17-23 July 2010. In Basic & Clinical Pharmacology & Toxicology, 2010, v. 107, suppl. 1, p. 149-

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