Pivoted Role of Protein Kinase Cδ in Angiotensin II–Induced Endothelial Cyclooxygenase-2 Expression
A Link to Vascular Inflammation
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.
Conclusion—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.
- Received September 7, 2010.
- Accepted January 31, 2011.
- © 2011 American Heart Association, Inc.