COX-2 expression stimulated by Angiotensin II depends upon AT1 receptor internalization in vascular smooth muscle cells.
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.
Morinelli
Thomas A
TA
Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. morinelt@musc.edu
Walker
Linda P
LP
Ullian
Michael E
ME
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*
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