Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System Role of Angiotensin II Type 1 Receptor and Peroxisome Proliferator Activated Receptor Signaling During Endothelial Aging

Telmisartan, in addition to blocking angiotensin (Ang) II type 1 receptor (AT1R), activates peroxisome proliferator activated receptor (PPAR ) signaling that interferes with nitric oxide (NO) system. Because aging of endothelial cells (ECs) is hallmarked by a reduction in NO synthesis, we hypothesized that telmisartan increases NO formation by regulated asymmetrical dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)system through blocking AT1R and activating PPAR signaling. To test this hypothesis, ECs were cultured with telmisartan, eprosartan, Ang II, and GW9662 (PPAR antagonist) until the twelfth passage. During the process of aging, PPAR protein expression decreased significantly, whereas the expression of AT1R increased. Telmisartan reversed these effects and dose-dependently decreased reactive oxygen species and 8-iso-prostaglandin (PG) F2 formation. This effect was associated with an upregulated activity and protein expression of DDAH, accompanied by a decrease in ADMA concentration, an increase in NO metabolites, and delayed senescence. Blockade of PPAR signaling by GW9662 or PPAR small-interference RNA prevented the effect of telmisartan on ADMA-DDAH-NO system. Coincubation with Ang II did not affect the effect of telmisartan-delayed senescence, whereas Ang II itself accelerated endothelial aging. Moreover, AT1R blocker eprosartan that did not influence PPAR protein expression had no effect on ADMA system and senescence. We have demonstrated that telmisartan mainly by activating PPAR signaling can alter the catabolism and release of ADMA as an important cardiovascular risk factor. We therefore propose that telmisartan translationally and posttranslationally upregulated DDAH expression via activation of PPAR signaling, causing ADMA to diminish and increase NO synthesis sufficient to delay senescence. (Hypertension. 2008;51:696-703.)