The benefit of docosahexanoic acid on the migration of vascular smooth muscle cells is partially dependent on Notch regulation of MMP-2/-9.
The Notch pathway is involved in the regulation of the migratory/proliferative phenotype acquired by vascular smooth muscle cells (VSMCs) in the pro-inflammatory context of vascular diseases. Here, we investigated whether docosahexaenoic acid (DHA), a polyunsaturated, omega-3 fatty acid, could reduce fibrinolytic/matrix-metalloproteinase (MMP) activity and whether this reduction occurs through the modulation of Notch signaling. Rat VSMCs were transdifferentiated with interleukin-1beta and then treated with DHA. Migration/proliferation was determined by performing a wound healing assay and measuring MMP-2/-9 activity, type 1 plasminogen activator inhibitor levels, and the expression of these proteins. The involvement of Notch in regulating the fibrinolytic/MMP system was evidenced using Notch pathway inhibitors and the forced expression of Notch1 and Notch3 intracellular domains. DHA significantly decreased VSMC migration/proliferation induced by interleukin-1beta as well as fibrinolytic/MMP activity. Prevention of Notch1 target gene transcription enhanced the interleukin-1beta effects on MMPs and on migration, whereas Notch3 intracellular domain overexpression reduced these effects. Finally, DHA increased Notch3 expression, Hes-1 transcription (a Notch target gene), and enhanced gamma-secretase complex activity. These results suggest that inhibition of the Notch pathway participates in the transition of VSMCs toward a migratory phenotype. These results also suggest that the beneficial inhibitory effects of DHA on fibrinolytic/MMP activity are related in part to the effects of DHA on the expression of Notch pathway components, providing new insight into the mechanisms by which omega-3 fatty acids prevent cardiovascular diseases.
Delbosc
Sandrine
S
UMR 7079: Physiologie et physiopathologie, CNRS, Université Pierre et Marie Curie, 7, quai Saint Bernard, 75005 Paris Cedex, France.
Glorian
Martine
M
Le Port
Anne-Sophie
AS
Béréziat
Gilbert
G
Andréani
Marise
M
Limon
Isabelle
I
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004789:Enzyme Activation; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D004281:Docosahexaenoic Acids; D018398:Homeodomain Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D017395:Plasminogen Activator Inhibitor 1; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489735:Hes1 protein, rat; C522363:Mmp2 protein, rat