Xi'an Jiaotong University Cardiovascular Research Center, Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Department of Pathophysiology, School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China.
Int J Mol Med. 2018 Jan;41(1):439-445. doi: 10.3892/ijmm.2017.3242. Epub 2017 Nov 7.
Silent information regulator family protein 1 (Sirt1) has recently gained attention for its protective effects against diabetic and cardiovascular diseases (CVDs). Vascular smooth muscle endothelin type B (ETB) receptors are involved in the pathogenesis of CVDs and diabetes. The aim of present study was to explore whether Sirt1 is involved in high glucose (HG)-mediated regulation of ETB receptors in rat superior mesenteric arteries (SMA). The rat SMA segments were cultured in the presence and absence of HG with or without the activator of Sirt1 and specific inhibitor for the extracellular signal-regulated protein kinase 1/2 (ERK1/2) for 24 h. Following organ culture, the contractile responses to sarafotoxin 6c were studied using a sensitive myograph, and the ETB receptor protein expression level was determined using western blotting. The results demonstrated that HG induced upregulation of ETB receptor expression and increased receptor-mediated vasoconstriction in SMA. Resveratrol (Res; a Sirt1 activator) concentration-dependently inhibited the HG-induced upregulation of ETB receptor expression and receptor-mediated vasoconstriction. Additionally, these effects could also be abolished by an inhibitor of the ERK1/2 signaling pathway. Furthermore, upregulation of ERK1/2 phosphorylation induced by HG was inhibited by Res. In conclusion, HG upregulated ETB receptors by downregulating Sirt1 and subsequently activating the ERK1/2 signaling pathways in the organ culture SMA.
沉默信息调节家族蛋白 1（Sirt1）最近因其对糖尿病和心血管疾病（CVDs）的保护作用而受到关注。血管平滑肌内皮素 B 型（ETB）受体参与 CVDs 和糖尿病的发病机制。本研究旨在探讨 Sirt1 是否参与高葡萄糖（HG）介导的大鼠肠系膜上动脉（SMA）中 ETB 受体的调节。将大鼠 SMA 段在存在和不存在 HG 以及 Sirt1 激活剂和细胞外信号调节蛋白激酶 1/2（ERK1/2）的特异性抑制剂的情况下培养 24 小时。器官培养后，使用灵敏的肌描记器研究沙夫托毒素 6c 引起的收缩反应，并使用 Western blot 测定 ETB 受体蛋白表达水平。结果表明，HG 诱导 ETB 受体表达上调，并增加 SMA 中受体介导的血管收缩。白藜芦醇（Res；Sirt1 激活剂）浓度依赖性抑制 HG 诱导的 ETB 受体表达上调和受体介导的血管收缩。此外，ERK1/2 信号通路的抑制剂也可以消除这些作用。此外，HG 诱导的 ERK1/2 磷酸化上调被 Res 抑制。总之，HG 通过下调 Sirt1 并随后激活器官培养 SMA 中的 ERK1/2 信号通路来上调 ETB 受体。
