Biosynthesis of proresolving lipid mediators by vascular cells and tissues

Abstract

Recent evidence suggests that specialized proresolving lipid mediators (SPMs) generated from docosahexaenoic acid (DHA) can modulate the vascular injury response. However, cellular sources for these autacoids within the vessel wall remain unclear. Here, we investigated whether isolated vascular cells and tissues can produce SPMs and assessed expression and subcellular localization of the key SPM biosynthetic enzyme 5-lipoxygenase (LOX) in vascular cells. Intact human arteries incubated with DHA produced 17-hydroxy DHA (17-HDHA) and D-series resolvins, as assessed by liquid chromatography-tandem mass spectrometry. Addition of 17-HDHA to human arteries similarly increased resolvin production. Primary cultures of human saphenous vein endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) converted 17-HDHA to SPMs, including resolvin D1 (RvD1) and other D-series resolvins and protectins. This was accompanied by a rapid translocation of 5-LOX from nucleus to cytoplasm in both ECs and VSMCs, potentially facilitating SPM biosynthesis. Conditioned medium from cells exposed to 17-HDHA inhibited monocyte adhesion to TNF-α-stimulated EC monolayers. These downstream effects were partially reversed by antibodies against the RvD1 receptors ALX/FPR2 and GPR32. These results suggest that autocrine and/or paracrine signaling locally generated SPMs in the vasculature may represent a novel homeostatic mechanism of relevance to vascular health and disease.-Chatterjee, A., Komshian, S., Sansbury, B. E., Wu, B., Mottola, G., Chen, M., Spite, M., Conte, M. S. Biosynthesis of proresolving lipid mediators by vascular cells and tissues.

Pro-resolving lipid mediators in vascular disease

“…SPMs have been identified in atherosclerotic lesions of mice (20,94). In recent work, we demonstrated that isolated, ex vivo human artery segments and primary cultured human vascular cells generated D-series resolvins and maresins when the relevant fatty acid precursors (e.g., DHA, 17-hydroxydocosahexaenoic acid ) were made available, and in the absence of leukocytes (95). Furthermore, conditioned media from DHA-supplemented vascular cells blunted leukocyte adhesion to cytokine-activated ECs, in a receptor-dependent fashion (i.e., ALX/FPR2 and GPR32).…”

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

“…SPM have been identified in mouse atherosclerotic lesions (Fredman, Hellmann et al 2016, Viola, Lemnitzer et al 2016) where they correlate with histologic signs of plaque stability. More recently it was demonstrated that isolated human artery segments and primary cultured human vascular cells generate D-series resolvins in the presence of precursors (DHA,17-HDHA) (Chatterjee, Komshian et al 2017). Conditioned media from these DHA-supplemented vascular cells blunted leukocyte adhesion to activated EC, in a reaction that was attenuated by blocking the RvD1 receptors ALX and GPR32.…”

“…Third, biosynthesis pathways for both omega-3 and omega-6 fatty acids are complex and involve competition for enzymes to production various bioactive mediators (Levy, Clish et al 2001, Serhan 2007, Spite and Serhan 2010, Merched, Serhan et al 2011, Colas, Shinohara et al 2014, Serhan 2014, Poorani, Bhatt et al 2015) and this competition can produce isomers without proresolving actions (Dona, Fredman et al 2008, Spite, Norling et al 2009). Furthermore, similar pathways might play antagonistic roles in different cell types and/or different species (Wittwer and Hersberger 2007, Chatterjee, Komshian et al 2017) and additional factors such as aging (common in the atherosclerosis population) may alter the biosynthetic pathways (Halade, Kain et al 2016). An additional consideration is that oral administration of precursors might not produce adequate systemic or local amounts of specific bioactive mediators (Endo, Sano et al 2014), especially in the setting of a high cholesterol diet (Faggin, Puato et al 2000).…”

Leukocytes from obese individuals exhibit an impaired SPM signature

“…Indeed, at the preclinical level, therapeutic administration of SPMs has shown to promote resolution of inflamed adipose tissue and to protect mice against obesity-associated complications such as insulin resistance and NAFLD (8)(9)(10)(11)(12). Moreover, recent findings have demonstrated that SPMs play a homeostatic role in the human vasculature (13). However, at present, clear proof that the production of SPMs is impaired in the systemic circulation of obese subjects is still lacking.…”