COX-2 expression stimulated by Angiotensin II depends upon AT1 receptor internalization in vascular smooth muscle cells

• Published in: Biochimica et biophysica acta 2008-06, Vol.1783 (6), p.1048-1054
• Main Authors: Morinelli, Thomas A., Walker, Linda P., Ullian, Michael E.
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II - pharmacology; Animals; Aorta, Thoracic - cytology; Arsenicals - pharmacology; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Cyclooxygenase 2; Cyclooxygenase 2 - metabolism; Endocytosis; G protein-coupled receptor; Immunoblotting; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Radioligand Assay; Rats; Receptor, Angiotensin, Type 1 - metabolism; Signal transduction; Vasoconstrictor Agents - pharmacology
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2008.01.012

Previously, we demonstrated that nuclear localization of the Angiotensin II AT1A receptor was associated with the activation of transcription for the COX-2 gene, PTGS-2. The hypothesis of the present study is that AT1AR internalization from the plasma membrane is a first step in the nuclear localization of the endogenous AT1AR of rat aortic vascular smooth muscle cells and the resultant increase of COX-2 protein expression. Angiotensin II produced both a time- and concentration-dependent increase in COX-2 protein expression in these cells. Treatment with sucrose or phenylarsine oxide, inhibitors of receptor internalization, significantly inhibited AT1AR internalization and abolished the increase in COX-2 protein produced by Angiotensin II without affecting COX-2 expression on its own. Sucrose pre-treatment of rat aortic vascular smooth muscle cells resulted in an increase in p42/44 and p38 activation, while phenylarsine oxide pre-treatment activated only p38 kinase without inhibiting activation of p42/44 produced by Angiotensin II. These results demonstrate that inhibiting the internalization of the AT1AR results in a loss of ability of Angiotensin II to increase the protein expression of COX-2, thus supporting previous work showing a relationship between AT1AR nuclear localization and activation of COX-2 gene expression. Surprisingly, in contrast to other studies, the data also indicates that activation of p42/44 and/or p38 does not correlate with the increased expression of COX-2.