title: COX-2 expression stimulated by Angiotensin II depends upon AT1 receptor internalization in vascular smooth muscle cells.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. morinelt@musc.edu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Morinelli
authors.forename: Linda P
authors.initials: LP
authors.lastname: Walker
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ullian
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001152:Arsenicals / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015151:Immunoblotting; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D001152:Arsenicals; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3