Abstract 11587: Acidosis/GPR4 Signaling Regulates Inflammatory and Endoplasmic Reticulum Stress Responses in Vascular Endothelial Cells
An acidotic tissue microenvironment is commonly found in ischemic organs, inflammatory sites, solid tumors, and in many other pathophysiological conditions. Due to hypoxia, glycolytic cell metabolism, and poor blood perfusion, production and accumulation of protons derived from lactic acid and other metabolic products acidify the microenvironment. Acidosis is an important stress factor that aggravates ischemic tissue injury and modulates the function of blood vessels and immune cells. Recent studies show that acidotic activation of the pH-sensing G protein-coupled receptor 4 (GPR4) increases endothelial cell inflammation and leukocyte adhesion. Numerous inflammatory genes such as adhesion molecules, chemokines, cytokines, NF-κB factors, and cyclooxygenase 2 are up-regulated by acidosis and GPR4 in endothelial cells. However, the signaling pathways by which acidosis/GPR4 regulates the inflammatory responses of endothelial cells are largely unknown. Using genetic and biochemical approaches we demonstrate that Gs, Gq and G13 G protein pathways are imperative for acidosis/GPR4-induced inflammatory gene expression in endothelial cells. Each of these G protein pathways controls the expression of a subset of the inflammatory target genes. Moreover, interaction between these G protein pathways has been observed; e.g., induction of VCAM-1 by acidosis/GPR4 is positively regulated by the Gs pathway but negatively regulated by the G13 pathway. We also demonstrate that acidosis/GPR4 induces the endoplasmic reticulum (ER) stress response, a process closely associated with inflammation, in endothelial cells. Interestingly, treatment with a novel GPR4 small molecule inhibitor diminishes the acidosis-induced endothelial cell ER stress response. Together, these results suggest that acidosis/GPR4 signaling is a novel regulatory mechanism of endothelial cell inflammation and ER stress response. Inhibition of the GPR4 receptor may be exploited as potential new means to suppress inflammation associated with cardiovascular disorders.
- © 2013 by American Heart Association, Inc.