Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital,Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Pediatric Cardiac Surgery, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, China.
IUBMB Life. 2019 Dec;71(12):2010-2019. doi: 10.1002/iub.2151. Epub 2019 Aug 24.
Atherosclerosis is a common and deadly cardiovascular disease with extremely high prevalence. Areas of the vasculature exposed to oscillatory shear stress (OSS) or disturbed blood flow are particularly prone to the development of atherosclerotic lesions. In part, various mechanosensitive receptors on the surface of endothelial cells play a role in regulating the ability of the vasculature to cope with variations in blood flow patterns. However, the exact mechanisms behind flow-mediated endothelial responses remain poorly understood. Along with the development of highly specific receptor agonists, the class of G coupled-protein receptors has been receiving increasing attention as potential therapeutic targets. G coupled-protein receptor 81 (GPR81), also known as hydroxycarboxylic acid receptor 1 (HCA ), is activated by lactate, its endogenous ligand. In the present study, we show for the first time that expression of GPR81 is significantly downregulated in response to OSS in endothelial cells and that activation of GPR81 using physiologically relevant doses of lactate can rescue OSS-induced reduced GPR81 expression. Importantly, our findings demonstrate that activation of GPR81 can exert valuable atheroprotective effects in endothelial cells exposed to OSS by reducing oxidative stress and significantly downregulating the expression of inflammatory cytokines including interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and high mobility group box 1 (HMGB1). We also show that activation of GPR81 can potentially prevent the attachment of monocytes to the endothelium by suppressing OSS-induced secretion of vascular cellular adhesion molecule (VCAM)-1 and endothelial-selectin (E-selectin). Finally, we show that activation of GPR81 can rescue OSS-induced reduced expression of the key atheroprotective transcription factor Kruppel-like factor 2 (KLF2), which is mediated through the extracellular-regulated kinase 5 (ERK5) pathway. These findings demonstrate a potential protective role of GPR81 against atherogenesis and that targeted activation of GPR81 may inhibit endothelial inflammation and dysfunction induced by OSS.
动脉粥样硬化是一种常见且致命的心血管疾病，其患病率极高。暴露于振荡剪切应力（OSS）或血流紊乱的血管区域特别容易发生动脉粥样硬化病变。部分原因是内皮细胞表面的各种机械敏感受体在调节血管适应血流模式变化的能力方面发挥作用。然而，血流介导的内皮反应的确切机制仍知之甚少。随着高特异性受体激动剂的发展，G 蛋白偶联受体（GPCR）类已成为潜在的治疗靶点，受到越来越多的关注。G 蛋白偶联受体 81（GPR81），也称为羟基羧酸受体 1（HCA1），被其内源性配体乳酸激活。在本研究中，我们首次表明，在血管内皮细胞中，GPR81 的表达在 OSS 作用下显著下调，并且使用生理相关剂量的乳酸激活 GPR81 可以挽救 OSS 诱导的 GPR81 表达下调。重要的是，我们的研究结果表明，在 OSS 作用下，激活 GPR81 可通过降低氧化应激和显著下调炎症细胞因子（包括白细胞介素（IL）-6、IL-8、单核细胞趋化蛋白（MCP）-1 和高迁移率族蛋白 1（HMGB1））的表达，对内皮细胞发挥有价值的抗动脉粥样硬化作用。我们还表明，通过抑制 OSS 诱导的血管细胞黏附分子（VCAM）-1 和内皮选择素（E-选择素）的分泌，激活 GPR81 可潜在地阻止单核细胞黏附在内皮细胞上。最后，我们表明，通过细胞外调节激酶 5（ERK5）途径，激活 GPR81 可挽救 OSS 诱导的关键抗动脉粥样硬化转录因子 Kruppel 样因子 2（KLF2）表达下调。这些发现表明 GPR81 在动脉粥样硬化形成中具有潜在的保护作用，靶向激活 GPR81 可能抑制 OSS 诱导的内皮炎症和功能障碍。
