Overview of posters presented during EAS 2010

Overview of posters presented during EAS 2010

 Postprandial changes in HDL particle metabolism and function in mixed dyslipidemia: possible therapeutic targets 

Lipid and cholesterol metabolism in the postprandial phase is associated with both quantitative and qualitative remodelling of HDL particle subspecies that may influence their antiatherogenic functions in the reverse cholesterol transport pathway. This study evaluated the capacity of whole plasma or isolated HDL particles to mediate cellular free cholesterol efflux, cholesteryl ester transfer protein (CETP)-mediated CE transfer and selective hepatic CE uptake during the postprandial phase in subjects with mixed dyslipidemia. Postprandially, cellular cholesterol efflux was preferentially enhanced through both scavenger receptor class BI (SR-BI) and ATP binding cassette transporter G1 (ABCG1) pathways, CETP-mediated transfer of CE from HDL to triglyceride-rich lipoprotein (TRL) particles was significantly elevated and hepatic uptake of HDL-CE via SR-BI was diminished. Considered together, these findings strongly suggest that postprandial changes in HDL particle metabolism and function in mixed dyslipidemia may constitute a therapeutic target to attenuate the pro-atherogenic features of postprandial lipemia in dyslipidemic subjects at high cardiovascular risk.

Julia Z, Duchene E, Fournier N et al. Potential atherogenicity of postprandial lipemia in mixed dyslipidemia : therapeutic target for CETP inhibition. Abstract 3.22. 78TH EAS Congress, Hamburg, Germany, 20-23 June 2010.

 Low plasma levels of HDL-C levels are prevalent in statin-treated patients 

In this cohort of the DYSlipidaemia International Study (DYSIS) (n=3710, 50% not at LDL cholesterol goal), low plasma levels of HDL cholesterol were common, especially among patients with, or at high risk of, cardiovascular disease (24%). Low plasma levels of HDL-C could therefore be partly responsible for the high residual cardiovascular risk of this population.

Millan J, Gonzalez-Juanatey JR, Alegria E et al. Prevalence of low HDL-C in statin-treated patients: the Dyslipidemia International Study (DYSIS-Spain). Abstract 2.65. 78TH EAS Congress, Hamburg, Germany, 20-23 June 2010.

 Relevance of HDL-C raising in statin-treated patients 

In this retrospective cohort analysis in 17,923 statin-treated patients followed for an average of 1.9 years, there were 815 cardiovascular events, and 220 cerebrovascular events. In adjusted Cox regression analysis, each 5 mg/dL increase in HDL-C was associated with a 6% decrease in risk for cardiovascular events (HR, 0.94; 95% CI, 0.90, 0.98). A similar association was reported for cerebrovascular events. These findings add to the evidence-base showing that increases in HDL-C are associated with a significantly decreased risk of experiencing cardiovascular events.

Bash L, Ambegaonkar B, Wenworth C, May C. Association between change in HDL and vascular events in statin treated patients: report from the UK General Practice Research Database. Abstract 2.51. 78TH EAS Congress, Hamburg, Germany, 20-23 June 2010

 Scavenger receptor CD36 may play a role in HDL metabolism 

Evidence suggests that scavenger receptor CD36-deficient mice (knockout mice) may have higher plasma levels of HDL cholesterol compared with wildtype mice. While CD36 binds HDL in vitro, the function of CD36 in HDL metabolism is controversial at present. The role of CD36 was investigated in H1299 cells. Murine CD36 was expressed with a recombinant adenovirus (Ad-mCD36) which mediates the expression of this receptor. CD36 induced an increase in HDL particle uptake, and this was significantly stimulated by murine CD36 expression, suggesting an increase in cellular HDL CE uptake. Selective CE uptake from HDL also increased significantly dependent on the dose of Ad-mCD36. These findings indicate that, in vitro, CD36 promotes the internalisation of HDL holo-particles and stimulates selective CE uptake from HDL, suggesting a role for CD36 in HDL metabolism.

Brundert M, Groitl P, Heeren J et al. Scavenger receptor CD36 mediates HDL selective cholesteryl ester uptake and HDL particle internalisation. Abstract 3.19. 78TH EAS Congress, Hamburg, Germany, 20-23 June 2010.

 Rational design of apoA-I mimetics needed 

ApoA-I mimetic peptides are promising anti-atherosclerotic agents, but how the structural features of these peptides relate to the multiple anti-atherogenic functions of HDL is poorly understood. Twenty two bi-helical apoA-I mimetic peptides were investigated in vitro for their capacity and specificity to promote cholesterol efflux, inhibit inflammatory responses in monocytes and endothelial cells and inhibit low density lipoprotein (LDL) oxidation. There were different optimal structural requirements for cholesterol efflux, anti-inflammatory properties and antioxidant properties. The researchers concluded that rational design of apoA-I mimetic peptides may substantially improve their therapeutic value and may lead to a better understanding of the anti-atherogenic functions of HDL.

Sviridov D, D'Souza W, Stonik JA et al. Stucture-function relationships of apolipoprotein A-I mimetic peptides: implications for anti-atherogenic activities of high density lipoprotein. Abstract 3.82. 78TH EAS Congress, Hamburg, Germany, 20-23 June 2010.

 Adiponectin and HDL

Previous studies showed a positive correlation between plasma HDL-C and adiponectin (APN) concentrations in humans, with plasma APN levels decreased in patients with coronary artery disease and metabolic syndrome. This study showed that APN up-regulated the mRNA and protein levels of ApoA-I and ABCA1 in HepG2 cells. Additionally, expression of the transcription factor COUP-TFII, and LXR-alpha were also significantly increased by APN. In HepG2 cells, knockdown of COUP-TFII by siRNA reduced the APN-induced enhancement of ApoA-I but not ABCA1 expression. These findings suggest that APN might protect against atherosclerosis by enhancing de novo hepatic HDL synthesis through both COUP-TFII- and LXR-alpha-dependent pathways.

Tsubakio-Yamamoto K, Ohama T, Masuda D et al. Adiponectin enhances de novo hepatic HDL synthesis through LXR alpha- and coup-TFII-dependent pathways. Abstract 3.88. 78TH EAS Congress, Hamburg, Germany, 20-23 June 2010.

 Structural requirements for apoA-I –ABCA interactions 

This study investigated transendothelial apoA-I transport in wild type (WT) apoA-I and apoA-I mutants. The C-terminal deletion mutant, apoA-I(Δ185-243), which cannot induce ABCA1- dependent lipid efflux from macrophages, showed 50% reduced total binding and no specific binding. The specific transendothelial transport of this mutant was reduced by 90%. However, transendothelial transport was unaffected in two mutants (N-terminal deletion mutant apoA-I(Δ1-59) and double deletion mutant apoA-I(Δ1-59,Δ185-243)). These data suggest that the C-terminal region is important for the specific interactions of apoA-I with ABCA1.

Ohnsorg P, Rohrer L, Chroni A et al. Interactions of apolipoprotein A-I mutants with endothelial cells. Abstract 3.132. 78TH EAS Congress, Hamburg, Germany, 20-23 June 2010.