The Pro-Resolving Lipid Mediator Maresin 1 (MaR1) Attenuates Inflammatory Signaling Pathways in Vascular Smooth Muscle and Endothelial Cells

Objective: Inflammation and its resolution are central to vascular injury and repair. Maresins comprise a new family of bioactive lipid mediators synthesized from docosahexaenoic acid, an omega-3 polyunsaturated fatty acid. They have been found to exert anti-inflammatory and pro-resolving responses in macrophages, neutrophils and bronchial epithelial cells and impart beneficial actions in murine models of peritonitis and colitis. We investigated the impact of maresin-1 (MaR1) on tumor necrosis factor alpha (TNF-alpha) induced inflammatory responses in human vascular endothelial (EC) and smooth muscle cells (VSMC). Methods: Primary cultures of human saphenous vein EC and VSMC were employed. We tested the naturally occurring MaR1 as modulator of TNF-alpha effects, with examination of monocyte adhesion, oxidant stress, and intracellular inflammatory signaling pathways. Results: MaR1 attenuated TNF-alpha induced monocyte adhesion and reactive oxygen species (ROS) generation in both EC and VSMC, associated with down-regulated expression (cell surface) of the adhesion molecule E-selectin (in EC) and NADPH-oxidases (NOX4, NOX1, NOX2). MaR1 attenuated TNF-alpha induced release of pro-inflammatory mediators by EC and VSMC. MaR1 caused an attenuation of TNF-a induced NF-kappa B activation in both cell types associated with inhibition of I-kappa Kinase (IKK) phosphorylation, I kappa B-alpha degradation and nuclear translocation of the NF-kappa B p65 subunit. MaR1 also caused a timedependent increase in intracellular cyclic AMP (cAMP) in both naive and TNF-alpha stimulated VSMC and EC. Conclusions: MaR1 has broad anti-inflammatory actions on EC and VSMC, which may be partly mediated through upregulation of cAMP and down-regulation of the transcription factor NF-kappa B. The results suggest that the pro-resolving lipid mediator MaR1 exerts homeostatic actions on vascular cells that counteract pro-inflammatory signals. These findings may have direct relevance for acute and chronic states of vascular inflammation.