Huang Y,  DiDonato JA, Levison BS, et al.
Nature Medicine (2014) doi:10.1038/nm.3459 Published online 26 January 2014

Background

HDL-c’s compositional heterogeneity  reflects its functional heterogeneity, including cholesterol acceptor activity, microRNA delivery and anti-inflammatory, anti-apoptotic, anti-thrombotic and innate immune functions [1-6]. Its lipid cargo-carrying function mainly depends on apolipoprotein A1 (apoA1), which constitutes about 75% of the protein content of HDL.
Inverse associations have been described for circulating HDL-c or apoA1 levels and coronary artery disease [7]. Recent studies that failed to show significant therapeutic benefit of HDL-elevating drugs, despite previously demonstrated anti-atherosclerotic effects of HDL-c, have revealed gap in our knowledge about HDL. It is suggested that HDL particle function, not HDL-c mass, is more clinically relevant both diagnostically and therapeutically. Recently it was shown that the biological function and HDL particle distribution of apoA1 within the artery wall was strikingly different from those of circulating apoA1 and HDL. ApoA1 in human aorta was found to contain low levels of lipids, not associated with HDL, and functionally impaired [8]. This study investigated molecular processes that impair apoA1 and HDL function in the artery wall and their value as diagnostic and therapeutic targets in cellular and murine models and in humans.

Main results

• One tryptophan residue (Trp72) in apoA1 was identified as a target for oxidation in the artery wall. This residue functions as an oxidative switch for impairing the cholesterol efflux activity of apoA1.
• Oxidised Trp72-apoA1 (oxTrp-apoA1) was detected in human atherosclerotic plaques but not in normal human aorta. OxTrp-apoA1 isolated from human aortic lesions is predominantly non-HDL associated and had negligible cholesterol efflux capacity.
• OxTrp-apoA1 is present in the circulation at very low levels, and does not associate with HDL.
• OxTrp-apoA1 isolated from the circulation of apparently healthy middle aged donors had proinflammatory effect on aortic endothelial cells, as monitored by clearly elevated levels of surface vascular cell adhesion molecule 1 (VCAM1) and endothelial cell nuclear factor-kappaB (NF-κB) activation.
• OxTrp-apoA1 is not specific to atherosclerotic plaque, but was also seen in another subacute inflammatory condition: a model for peritonitis. Thus, human apoA1 appears to be targeted for post-translational modification at Trp72 during subacute inflammation. 
• OxTrp-apoA1 recovered from human plasma is deficient in ABCA1-dependent HDL biogenesis activity in mice.
• In a cohort of subjects undergoing elective CV risk-factor evaluation, in which 35% had clinical evidence of CVD, showed substantial variation among subjects of plasma oxTrp-apoA1 and total apoA1 levels. While on average only 0.007% of apoA1 in plasma had the oxTrp-moiety, oxTrp-apoA1 represented 20% of total apoA1 in atherosclerotic plaque-laden aorta. Thus, it is over 1000-fold concentrated in plaques, as compared to plasma.
• Higher levels of circulating oxTrp-apoA1 (both absolute concentration and relative to total apoA1) were independently associated with increased CAD and CVD risk.

Conclusion

These combined cellular, murine and human studies identify the structural basis of an abundant dysfunctionals form of apoA1 and HDL within the artery wall. Site-specific oxidisation of a tryptophan residue in apoA1 makes that it hardly associated with HDL particles and renders it proinflammatory.
Since higher levels of oxTrp-apoA1 were also detected in another subacute inflammatory condition, the authors do not anticipate that circulating oxTrp-apoA1 could serve as a specific factor of atherosclerosis. Elevated levels did however associate with CAD and CVD risk, after correction for multiple traditional risk factors. Further studies need to explore the possibility that the proinflammatory activity of oxTrp-apoA1 renders it pro-atherogenic. Furthermore, oxTrp-apoA1 may be explored to serve as a new therapeutic target in CAD.

Find this article online

News • 28-1-2014 • Expert opinion

Erik Stroes: “Increasing HDLc as a therapy remains promising”

Prof.dr. E.S.G. Stroes (AMC Amsterdam) responds to an article published in Nature Medicine on Januari 26 on dysfunctional and proinflammatory apoA1, elsewhere on this website.

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