Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT₂ and CysLT₁ receptors

Sci Rep. 2013 Nov 20:3:3274. doi: 10.1038/srep03274.

Abstract

Cysteinyl leukotrienes (cys-LTs), LTC₄, LTD₄, LTE₄ are potent inflammatory lipid mediators that act through two distinct G-protein-coupled receptors, CysLT₁R and CysLT₂R. Although cys-LTs are shown to induce vascular leakage and atherosclerosis, the molecular mechanism by which cys-LTs modulate endothelial function is not known. Here, we show that cys-LTs (LTC₄ and LTD₄) induce robust calcium influx in human umbilical vein endothelial cells (HUVECs) through CysLT₂R, but not CysLT₁R. Further, cys-LT treatment induced endothelial cell (EC) contraction leading to monolayer disruption via CysLT₂R/Rho kinase dependent pathway. Furthermore, stimulation with cys-LTs potentiated TNFα-induced VCAM-1 expression and leukocyte recruitment to ECs through CysLT₂R. In contrast, we found that both LTC₄ and LTD₄ stimulated EC proliferation through CysLT₁R. Taken together, these results suggest that cys-LTs induce endothelial inflammation and proliferation via CysLT₂R/Rho kinase and CysLT₁R/Erk dependent pathways, respectively, which play critical role in the etiology of cardiovascular diseases such as atherosclerosis and myocardial infarction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Calcium Signaling
  • Cell Proliferation / drug effects
  • Cysteine / pharmacology*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Leukotrienes / pharmacology*
  • Receptors, Leukotriene / metabolism*
  • Signal Transduction / drug effects*
  • Tumor Necrosis Factor-alpha / pharmacology
  • rho-Associated Kinases / metabolism

Substances

  • Leukotrienes
  • Receptors, Leukotriene
  • Tumor Necrosis Factor-alpha
  • cysteinyl-leukotriene
  • cysteinyl leukotriene receptor 2
  • rho-Associated Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Cysteine
  • leukotriene D4 receptor
  • Calcium