Activation of GPR81 by lactate inhibits oscillatory shear stress-induced endothelial inflammation by activating the expression of KLF2

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(1)), 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.