Leukotriene B4 mediates vascular smooth muscle cell migration through αvβ3 integrin transactivation.
Vascular injury leads to a local inflammatory response, characterized by endothelial damage, extracellular matrix exposition and aggregation/adhesion of platelets and circulating leukocytes. The release of inflammatory mediators amplifies the process, and can induce vascular smooth muscle cells (SMC) migration and proliferation. Released by leukocytes, leukotriene B4 (LTB4) induces reactive oxygen species production and SMC chemotaxis. This study was conducted to elucidate the molecular mechanisms involved in the effect of LTB4 on SMC migration, and a rat linage of vascular SMC (A7r5) were used throughout. The chemotactic effect of LTB4 was dependent on the concentration used, being comparable to AngII at 100 nM. Migration induced by LTB4 was inhibited in the presence of pertussis toxin, CP-105696, a BLT1 receptor antagonist, and by LY294002 or PD98059, two inhibitors of PI3K and MEK1/2, respectively. Stimulation of SMC with LTB4 triggered integrin-associated signaling pathways, inducing focal adhesion kinase (FAK) phosphorylation, mobilization of actin cytoskeleton, association of FAK to PI3K, ERK-2 phosphorylation and nuclear translocation, and also NFκB pathway activation. Pretreatment of SMC with a selective ligand of αvβ3 integrin, kistrin, inhibited LTB4-induced chemotaxis, FAK phosphorylation, FAK-PI3K association, and also inhibited ERK-2 and NFκB pathways activation. Taken together, the data demonstrated, for the first time, that the effect of LTB4 on SMC migration is modulated by integrin signaling activation, suggesting that these adhesion molecules might be important target for therapeutic intervention in cardiovascular diseases.
Moraes
João
J
Departamento de Farmacologia, Universidade do Estado do Rio de Janeiro, UERJ, Rio de Janeiro, RJ, Brazil.
Assreuy
Jamil
J
Canetti
Cláudio
C
Barja-Fidalgo
Christina
C
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002633:Chemotaxis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007975:Leukotriene B4 / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D015533:Transcriptional Activation; D057772:Vascular System Injuries / Q000378:metabolism
D004791:Enzyme Inhibitors; D039302:Integrin alphaVbeta3; D007975:Leukotriene B4; D019255:NADPH Oxidases