Clin Res Cardiol 96: Suppl 1 (2007)

V1475 - Influence of telmisartan on NO-asymmetric dimethylarginine (ADMA) system- Role of AT1R and PPARĪ³ signaling during endothelial aging
F. Scalera1, J. Martens-Lobenhoffer1, A. Bukowska2, M. Täger3, U. Lendeckel2, S. Bode-Böger1
1Institut für Klinische Pharmakologie, Universitätsklinikum Magdeburg, Magdeburg; 2Institut für Experimentelle Innere Medizin, Universitätsklinikum Magdeburg, Magdeburg; 3IMTM, Magdeburg;
Evidence is accumulating that telmisartan, in addition to blocking angiotensin II (Ang II) type 1 receptor (AT1R), activates peroxisome proliferator activated receptor γ (PPARγ ) which signaling interferes with the NO system. Because aging of endothelial cells is hallmarked by a reduction in NO synthesis, we hypothesized that telmisartan increases NO formation by regulated asymmetric dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH) system through blocking AT1 receptor or activating PPARγ signaling during endothelial aging. To test this hypothesis, endothelial cells were cultured until the twelfth passage. Telmisartan, Ang II and GW9662 (PPARγ antagonist) were replaced every 48 hours starting at the fourth passage. Telmisartan dose-dependently decreased ROS and 8-iso-prostaglandin F formation, and up-regulated the activity and expression of DDAH, accompanied by a decrease in ADMA concentration and an increase NO metabolite in culture media. During the process of endothelial aging, PPARγ protein expression decreased significantly, whereas the protein expression of AT1R increased. Telmisartan reversed these effects. Activating of AT1R signaling by Ang II or blockade of PPARγ signaling by GW9662 prevented the effect of telmisartan on ADMA-DDAH-NO system. We have demonstrated that the ability of telmisartan both to block AT1R or to activate PPARγ signaling can alter the catabolism and release of ADMA as an important cardiovascular risk factor. We therefore propose that telmisartan posttranslationally upregulated DDAH activity via decreased oxidative stress, causing ADMA to diminish and increase NO synthesis. This may provide a therapeutic strategy aimed at blocking aging-induced NO inhibition.