Chylomicron remnants: mediators of endothelial dysfunction?

Abstract

Vascular disease is initiated by activation of the endothelium characterized by the predominance of pro-inflammatory and pro-coagulant changes in endothelial cells (ECs) referred to collectively as 'endothelial dysfunction'. There is increasing evidence that lipoproteins of dietary origin modulate EC function and the use of artificial chylomicron remnant-like particles (CRLPs) in vitro is now beginning to shed light on the molecular mechanisms through which these particles influence cell behaviour. CRLPs enriched in n-6 PUFAs (polyunsaturated fatty acids) influence the production of vasoactive mediators by ECs in a pro-inflammatory manner. Thus CRLPs reduce the synthesis and release of nitric oxide and alter the balance of release of vasodilator versus vasoconstrictor eicosanoids. These changes are accompanied by induction of cyclo-oxygenase-2 expression and activity as well as increased expression of adhesion molecules and the antioxidant defence enzyme haem oxygenase-1. CRLPs also activate a number of intracellular signalling pathways, including NF-kappaB (nuclear factor kappaB) and MAPKs (mitogen-activated protein kinases), which may be involved in mediating their effects on gene expression. The effects of CRLPs on EC behaviour can also be modulated by the type of fat/oxidation status of the particles. These findings support the hypothesis that lipoproteins of dietary origin directly regulate molecular events in the vascular wall.

Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways

“…This process results in TGRL remnant particle formation and lipolysis products such as phospholipids and fatty acids. Previous studies have shown that TGRL lipolysis products cause aortic endothelial injury, including inflammation, elevated expression of reactive oxygen species (ROS), and increased vascular permeability (22)(23)(24)(25)(26)(27)(28)(29). Additionally, activating transcription factor (ATF) 3 appears to play an important role as a master regulator of inflammation in the aortic endothelium in response to TGRL lipolysis products (22,30).…”

Understanding Postprandial Inflammation and Its Relationship to Lifestyle Behaviour and Metabolic Diseases

“…This reduction of FMD correlated with TG and FFA concentrations and was reversible when TG concentrations decreased at the end of the oral fat loading test [57]. Furthermore, postprandial TRLs have been shown to induce the expression of leukocyte adhesion molecules on the endothelium, facilitating recruitment of inflammatory cells [59] and remnant lipoproteins have been found to activate endothelial cells by upregulating COX-2 expression and activating intracellular signaling pathways controlled by nuclear factor-kappaB and mitogen-activated protein kinases [60]. …”

Dietary saturated and unsaturated fats as determinants of blood pressure and vascular function

“…Remnant TAG-rich lipoproteins isolated from hyperlipidaemic subjects impaired endothelium-dependent relaxation in rabbit aortic strips ( 154 ) and levels of remnant TAG-rich lipoproteins were associated with impaired dilation of coronary arteries in human subjects, linked to NO bioavailability ( 155 ) . Some recent research using artificial chylomicron remnant-like particles has helped to resolve the molecular mechanisms that mediate postprandial effects on the endothelium, showing that these particles inhibit NO production from cultured endothelial cells, induce cyclo-oxygenase-2 activity, and increase expression of inflammatory molecules and antioxidant enzymes ( 156 ) .…”