Telmisartan activates endothelial nitric oxide synthase via Ser1177 phosphorylation in vascular endothelial cells.
Because endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.
Department of Cardiovascular Medicine, The University of Tokyo, Graduate school of Medicine, Tokyo, Japan.
Masahiro
M
Myojo
Department of Nephrology, Jichi Medical University, Tochigi, Japan.
Daisuke
D
Nagata
Department of Cardiovascular Medicine, The University of Tokyo, Graduate school of Medicine, Tokyo, Japan.
Daishi
D
Fujita
Department of Cardiovascular Medicine, The University of Tokyo, Graduate school of Medicine, Tokyo, Japan.
Arihiro
A
Kiyosue
Department of Cardiovascular Medicine, The University of Tokyo, Graduate school of Medicine, Tokyo, Japan.
Masao
M
Takahashi
Department of Cardiology and Nephrology, Dokkyo Medical University, Tochigi, Japan.
Hiroshi
H
Satonaka
Department of Nephrology, Jichi Medical University, Tochigi, Japan.
Yoshiyuki
Y
Morishita
Department of Nephrology, Jichi Medical University, Tochigi, Japan.
Tetsu
T
Akimoto
Jichi Medical University, Tochigi, Japan.
Ryozo
R
Nagai
Department of Cardiovascular Medicine, The University of Tokyo, Graduate school of Medicine, Tokyo, Japan.
Issei
I
Komuro
The Tokyo Teishin Hospital, Tokyo, Japan.
Yasunobu
Y
Hirata
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D013777:Tetrazoles; D000068756:Valsartan; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D006152:Cyclic GMP; D014633:Valine; D000077333:Telmisartan