Department of Regenerative Medicine and Cell biology

Research in Focus

Targeting Endothelial Barrier Dysfunction with HDL-S1P Therapeutics

Thus far, attempts at therapeutic elevation of HDL have not proved useful in reducing cardiovascular disease (CVD) risk in humans, despite evidence from epidemiological studies indicating that high levels of HDL cholesterol (HDL-C) inversely associate with risk for CVD.  Findings from the laboratory of Dr. Kelley Argraves indicate that compositional differences of sphingolipids carried by HDL are related to the occurrence of ischemic heart disease (IHD), and suggest that these differences may contribute to the putative protective role of HDL in IHD and other vascular disorders. Specifically researchers in the Argraves lab have found a highly significant inverse relationship between the level of sphingosine 1-phosphate (S1P) in the HDL-containing fraction of serum and the occurrence of IHD (1). These findings support the hypothesis that the atheroprotective activity of HDL is at least in part a function of S1P content, with higher levels being protective. This agrees with emerging evidence suggesting that many of the effects of HDL on cardiovascular function may be attributable to its S1P cargo. Research in the Argraves lab highlight the potential therapeutic utility of HDL-S1P or agents that augment HDL-S1P levels to combat EC barrier dysfunction and atherosclerosis. rif7

Levels of HDL-associated S1P dictate the magnitude of endothelial barrier activity. Confluent endothelial cell monolayers were incubated with native HDL (72 nM S1P) or HDL containing varying amounts of exogenously added S1P. HDL was added to achieve a final concentration of 250 mg protein/ml. As a control, monolayers were incubated with the vehicle buffer, 0.03 mM EDTA in Dulbecco's PBS (Control). Each of the trans endothelial electrical resistance/impedance tracings shown is an average from two replicates per treatment. Impedance values were normalized by dividing each value by the level of impedance measured just prior to the addition of effectors. The results depicted are representative of two independent experiments. From Argraves et al., Lipids Health Dis. 2011 May 9;10:70.

posted 9/28/2011

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