1. Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System
- Author
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Michael Täger, Fortunato Scalera, Jens Martens-Lobenhoffer, Stefanie M. Bode-Böger, Alicja Bukowska, and Uwe Lendeckel
- Subjects
Senescence ,medicine.medical_specialty ,Endothelium ,Down-Regulation ,Peroxisome proliferator-activated receptor ,Thiophenes ,Arginine ,Nitric Oxide ,Benzoates ,Receptor, Angiotensin, Type 1 ,Amidohydrolases ,Nitric oxide ,chemistry.chemical_compound ,Downregulation and upregulation ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Anilides ,Telmisartan ,Receptor ,Cells, Cultured ,Cellular Senescence ,chemistry.chemical_classification ,Angiotensin II ,Imidazoles ,Up-Regulation ,PPAR gamma ,Oxidative Stress ,medicine.anatomical_structure ,Endocrinology ,Acrylates ,chemistry ,Benzimidazoles ,Endothelium, Vascular ,Angiotensin II Type 1 Receptor Blockers ,Signal Transduction ,medicine.drug - Abstract
Telmisartan, in addition to blocking angiotensin (Ang) II type 1 receptor (AT 1 R), activates peroxisome proliferator activated receptor γ (PPARγ) 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 AT 1 R and activating PPARγ signaling. To test this hypothesis, ECs were cultured with telmisartan, eprosartan, Ang II, and GW9662 (PPARγ antagonist) until the twelfth passage. During the process of aging, PPARγ protein expression decreased significantly, whereas the expression of AT 1 R increased. Telmisartan reversed these effects and dose-dependently decreased reactive oxygen species and 8-iso-prostaglandin (PG) F 2α 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 PPARγ signaling by GW9662 or PPARγ 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, AT 1 R blocker eprosartan that did not influence PPARγ protein expression had no effect on ADMA system and senescence. We have demonstrated that telmisartan mainly by activating PPARγ 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 PPARγ signaling, causing ADMA to diminish and increase NO synthesis sufficient to delay senescence.
- Published
- 2008
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