AT1 receptor blocker potentiates shear-stress induced nitric oxide production via modulation of eNOS phosphorylation of residues Thr and Ser |
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Authors: | Valério G Barauna Pâmela R Mantuan Flávio C Magalhães Luciene CG Campos José E Krieger |
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Institution: | 1. Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-000, Brazil;2. Multicentric Program of Post-Graduation in Physiological Sciences, Department of Physical Education, Federal University of the Jequitinhonha and Mucuri Valleys, Diamantina 39100-000, Brazil |
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Abstract: | We tested the hypothesis that AT1R blockade modulates the shear stress-induced (SS) synthesis of nitric oxide (NO) in endothelial cells (EC). The AT1R blocker Candesartan in the absence of the ligand angiotensin II (ang II) potentiated SS-induced NO synthesis accompanied by increased p-eNOSSer1177 and decreased p-eNOSThr495. Candesartan also inhibited SS-induced ERK activation and increased intracellular calcium transient in a time-dependent manner. To confirm the role of ERK to modulate p-eNOSThr495 and calcium to modulate p-eNOSSer1177, the MEK inhibitor U0126 and the calcium chelator BAPTA-AM were used, respectively. Pre-treatment of EC with U0126 completed abrogated basal and SS-induced ERK activation, inhibited p-eNOSThr495 and increased NO production by SS. On the other hand, pre-treatment of EC with BAPTA-AM decreased the effects of SS alone or in combination with Candesartan to induce p-eNOSSer1177 and partially inhibited the effects of Candesartan to potentiate NO release by SS. The AT1R blockers Losartan and Telmisartan were also tested but only Telmisartan potentiated NO synthesis and blocked SS-induced AT1R activation. Altogether, we provide evidence that Candesartan and Telmisartan potentiate SS-induced NO production even in the absence of the ligand ang II. This response requires both the inhibition of eNOS phosphorylation at its inhibitory residue Thr495 as well as the increase of eNOS phosphorylation at its excitatory residue Ser1177. In addition, the response is associated with inhibition of SS-induced ERK activation as well as increasing intracellular calcium transient. One may speculate that these yet undescribed events may contribute to the benefits of ARBs in cardiovascular diseases. |
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Keywords: | Angiotensin type I receptor Shear stress eNOS Endothelial cell |
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