The benefit of docosahexanoic acid on the migration of vascular smooth muscle cells is partially dependent on Notch regulation of MMP-2/-9

Authors:
Delbosc S, Glorian M, Le Port AS, Bereziat G, Andreani M, Limon I
In:
Source: Am J Pathol
Publication Date: (2008)
Issue: 172(5): 1430-40
Research Area:
Cancer Research/Cell Biology
Dermatology/Tissue Engineering
Cells used in publication:
Aortic Smooth Muscle Cells (R-ASM), Rat
Species: rat
Tissue Origin: aortic
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
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.