Nitroglycerin-Induced Endothelial Dysfunction and Tolerance Involve Adverse Phosphorylation and S-Glutathionylation of Endothelial Nitric Oxide Synthase Beneficial Effects of Therapy With the AT(1) Receptor Blocker Telmisartan

作者：Knorr Maike; Hausding Michael; Kroeller Schuhmacher Swenja; Steven Sebastian; Oelze Matthias; Heeren Tjebo; Scholz Alexander; Gori Tommaso; Wenzel Philip; Schulz Eberhard; Daiber Andreas^*; Muenzel Thomas

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(10): 2223-U187.

DOI：10.1161/ATVBAHA.111.232058

• endothelial function
• nitric oxide synthase
• nitroglycerin
• superoxide

Objective-Continuous administration of nitroglycerin (GTN) causes tolerance and endothelial dysfunction by inducing reactive oxygen species (ROS) production from various enzymatic sources, such as mitochondria, NADPH oxidase, and an uncoupled endothelial nitric oxide synthase (eNOS). In the present study, we tested the effects of type 1 angiotensin (AT(1))-receptor blockade with telmisartan on GTN-induced endothelial dysfunction in particular on eNOS phosphorylation and S-glutathionylation sites and the eNOS cofactor synthesizing enzyme GTP-cyclohydrolase I.
Methods and Results-Wistar rats were treated with telmisartan (2.7 or 8 mg/kg per day PO for 10 days) and with GTN (50 mg/kg per day SC for 3 days). Aortic eNOS phosphorylation and S-glutathionylation were assessed using antibodies against phospho-Thr495 and Ser1177 or protein-bound glutathione, which regulate eNOS activity and eNOS-dependent superoxide production (uncoupling). Expression of mitochondrial aldehyde dehydrogenase was determined by Western blotting. Formation of aortic and cardiac ROS was assessed by fluorescence, chemiluminescence, and 3-nitrotyrosine/malondialdehyde-positive protein content. Telmisartan prevented endothelial dysfunction and partially improved nitrate tolerance. Vascular, cardiac, mitochondrial, and white blood cell ROS formation were significantly increased by GTN treatment and inhibited by telmisartan. GTN-induced decrease in Ser1177, increase in Thr495 phosphorylation or S-glutathionylation of eNOS, and decrease in mitochondrial aldehyde dehydrogenase expression were normalized by telmisartan.
Conclusion-These data identify modification of eNOS phosphorylation as an important component of GTN-induced endothelial dysfunction. Via its pleiotropic "antioxidant" properties, telmisartan prevents, at least in part, GTN-induced oxidative stress, nitrate tolerance, and endothelial dysfunction. (Arterioscler Thromb Vasc Biol. 2011;31:2223-2231.)

• 出版日期2011-10