title: Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT₂ and CysLT₁ receptors.
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.
authors.affiliation: Department of Chemistry, University of Akron, OH 44325.
authors.forename: Ernest
authors.initials: E
authors.lastname: Duah
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Adapala
authors.forename: Nosayba
authors.initials: N
authors.lastname: Al-Azzam
authors.forename: Vinay
authors.initials: V
authors.lastname: Kondeti
authors.forename: Farai
authors.initials: F
authors.lastname: Gombedza
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
authors.forename: Sailaja
authors.initials: S
authors.lastname: Paruchuri
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015289:Leukotrienes / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D015289:Leukotrienes; D018077:Receptors, Leukotriene; D014409:Tumor Necrosis Factor-alpha; C112381:cysteinyl-leukotriene; C412375:cysteinyl leukotriene receptor 2; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D003545:Cysteine; C083169:leukotriene D4 receptor; D002118:Calcium