Pivotal role of protein kinase Cdelta in angiotensin II-induced endothelial cyclooxygenase-2 expression: a link to vascular inflammation

Arterioscler Thromb Vasc Biol. 2011 May;31(5):1169-76. doi: 10.1161/ATVBAHA.110.216044. Epub 2011 Feb 10.

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.

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Angiotensin II / administration & dosage
  • Angiotensin II / metabolism*
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Atherosclerosis / enzymology*
  • Blotting, Western
  • Cells, Cultured
  • Chemokine CCL2 / metabolism
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Hypertension / chemically induced
  • Hypertension / enzymology
  • Hypertension / physiopathology
  • Hypertension / prevention & control
  • Inflammation / enzymology*
  • Inflammation Mediators / metabolism
  • Male
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / enzymology*
  • Middle Aged
  • Phosphorylation
  • Protein Kinase C-delta / antagonists & inhibitors
  • Protein Kinase C-delta / genetics
  • Protein Kinase C-delta / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Receptor, Angiotensin, Type 1 / metabolism
  • Signal Transduction
  • Time Factors
  • Tissue Culture Techniques
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • CCL2 protein, human
  • Chemokine CCL2
  • Cyclooxygenase 2 Inhibitors
  • Inflammation Mediators
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Ptgs2 protein, rat
  • Prkcd protein, rat
  • PRKCD protein, human
  • Protein Kinase C-delta
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases