title: Pivotal role of protein kinase Cdelta in angiotensin II-induced endothelial cyclooxygenase-2 expression: a link to vascular inflammation.
abstract: OBJECTIVE
  The purpose of this study was to examine the hypothesis that angiotensin II (Ang II) induced endothelial cyclooxygenase-2 (COX-2) expression, which in turn mediated the generation of proinflammatory cytokines.
  
  
  RESULTS
  Western blot analysis on primary rat endothelial cells showed Ang II induced COX-2 expression, which was abolished by cotreatment of p38 mitogen-activated protein kinase (SB 202190) and extracellular signal-regulated kinase 1/2 (PD 98059) inhibitors. Protein kinase Cδ (PKCδ) inhibitor (rottlerin) prevented extracellular signal-regulated kinase 1/2 phosphorylation and COX-2 expression. The pivotal role of PKCδ was further supported by a similar stimulatory effect of the PKC activator on COX-2 expression, signified by Ang II-stimulated translocation of PKCδ to the plasma membrane, and confirmed by PKCδ phosphorylation at Tyr311. Small interfering RNA targeting PKCδ diminished COX-2 expression, which was further abrogated by SB 202190. Human mesenteric arteries incubated with Ang II showed increased levels of endothelial COX-2 and monocyte chemoattractant protein-1; the former was inhibited by SB 202190 plus rottlerin, whereas the latter was prevented by COX-2 inhibitor.
  
  
  CONCLUSIONS
  The present study pinpoints a novel role of PKCδ in Ang II-induced endothelial COX-2 upregulation and identifies a COX-2-dependent proatherosclerotic cytokine monocyte chemoattractant protein-1. The findings raise the possibility of curtailing endothelial COX-2 expression as a means of limiting or preventing vascular inflammation.
authors.affiliation: Institute of Vascular Medicine, and School of Biomedical Sciences, Department of Surgery, Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region, China. christine_wong@cuhk.edu.hk
authors.forename: Siu Ling
authors.initials: SL
authors.lastname: Wong
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.forename: Wing Tak
authors.initials: WT
authors.lastname: Wong
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Chak Leung
authors.initials: CL
authors.lastname: Au
authors.forename: Chi Fai
authors.initials: CF
authors.lastname: Ng
authors.forename: Simon Siu Man
authors.initials: SS
authors.lastname: Ng
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology*; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D007249:Inflammation / Q000201:enzymology*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D052246:Cyclooxygenase 2 Inhibitors; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C489691:Ptgs2 protein, rat; C497260:Prkcd protein, rat; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases