AT1 receptor blocker potentiates shear-stress induced nitric oxide production via modulation of eNOS phosphorylation of residues Thr(495) and Seri(1177)

作者：Barauna Valerio G; Mantuan Pamela R; Magalhaes Flavio C; Campos Luciene C G; Kriegel Jose E^*

来源：Biochemical and Biophysical Research Communications, 2013, 441(4): 713-719.

DOI：10.1016/j.bbrc.2013.10.108

• Angiotensin type I receptor
• Shear stress
• eNOS
• Endothelial cell

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-eNOS(Ser1177) and decreased p-eNOS(Thr495). 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-eNOS(Thr495) and calcium to modulate p-eNOS(Ser1177), 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 ERI( activation, inhibited p-eNOS(Thr495) 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-eNOS(Ser1177) 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 Thr(495) as well as the increase of eNOS phosphoiylation at its excitatory residue Ser(1177). 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.

• 出版日期2013-11-29