N-3 long-chain polyunsaturated fatty acids inhibit smooth muscle cell migration by modulating urokinase plasminogen activator receptor through MEK/ERK-dependent and -independent mechanisms.
Smooth muscle cell (SMC) migration is a major and complex feature of atherosclerosis and restenosis. N-3 long-chain polyunsaturated fatty acids (LCPUFAs) affect SMC migration; however, the mechanisms involved are unclear. This study investigated the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the MEK/ERK pathway and urokinase plasminogen activator receptor (uPAR) in relation to SMC migration. Transwell migration assays revealed that both EPA and DHA decreased cell migration. Western blotting and real-time reverse transcription polymerase chain reaction showed that n-3 LCPUFAs decreased uPAR expression, but not urokinase plasminogen activator (uPA) expression, without changing plasmin and uPA activity. DHA also inhibited the activation of the MEK/ERK signaling pathway, whereas EPA switched the SMC phenotype from synthetic to contractile. siRNA technology targeting uPAR expression showed that decreased uPAR led to a significant decrease in migration, demonstrating the role of uPAR on SMC migration. We also showed that MEK/ERK pathway activation was involved in the regulation of uPAR gene expression in SMCs. Our results suggest that n-3 LCPUFAs decrease SMC migration through the inhibition of uPAR expression, with DHA affecting its expression via the modulation of MEK/ERK signaling pathway, while EPA induces a change in SMC phenotype. This could represent another means by which to explain how n-3 LCPUFAs exert their preventive properties against atherosclerosis.
The Rowett Institute of Nutrition and Health, The University of Aberdeen, AB21 9SB Aberdeen, UK.
Claire
C
Whyte
Frank
F
Thies
Lise
L
Peyrol
Denis
D
Balcerzak
D000293:Adolescent; D000328:Adult; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D015525:Fatty Acids, Omega-3; D010743:Phospholipids; D055293:Receptors, Urokinase Plasminogen Activator; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D014568:Urokinase-Type Plasminogen Activator