Oxidised ApoA1- A major step in atherosclerosis and CVD

A recent study by Huang and colleagues published in Nature Medicine has helped to elucidate the mechanism whereby 'good cholesterol' high density lipoproteins (HDLs) lose their cardioprotective function and contribute to inflammation, especially associated with risk of atherosclerosis (1). More than 75% of HDL is composed of apolipoprotein A1 (ApoA1) and it is this component that is essential for the beneficial effects of HDLs. Briefly, native HDLs have been shown to reduce inflammation, target cholesterol for degradation, increase cellular insulin sensitivity and inhibit coagulation (Gordts et al. 2014)(2). Understanding HDL loss-of- function in vivo may therefore assist the quest for therapeutic targets that maintain native cardioprotective HDL. Previous studies from CVD patients have shown ApoA1 in the artery wall to be oxidatively cross-linked and dissociated from HDLs. Myeloperoxidase (MPO), mainly derived from macrophages, is the major enzyme responsible for these modifications.

This study was the first to examine which site-specific modification of ApoA1 was responsible for its dysfunction. It was found that oxidation of tryptophan at codon 72  (Trp72) was oxidised by MPO, and this form recovered from patients was found to be lipid-poor and capable of inducing expression of inflammatory genes in endothelial cells, the first step to atherosclerosis. In addition, oxTrp-72 ApoA1 showed reduced cholesterol binding, thereby elevating circulating cholesterol levels. One of the most significant findings to emerge is that the oxTrp72 ApoA1 to native ApoA1 ratio in cardiology patients was a strong predictor of subsequent CVD and atherosclerosis incidence.

This study raises the possibility for using MPO as a therapeutic target while levels of oxTrp72 ApoA1 may be a useful prognostic indicator. Ronald et al. have already exploited MRI scanning that detects MPO activity in vivo to image areas of atherosclerotic inflammation noninvasively(3). Clearly, the mechanisms by which mediate HDL cardioprotection will continue to come to light, helping to treat an increasingly prevalent disease in the Western world.

References

1. Huang et al. An abundant dysfunctional apolipoprotein A1 in human atheroma Nature Medicine January 2014
2.  Gordts et al. Pleiotropic effects of HDL: Towards new therapeutic areas for HDL-targeted interventions Current Molecular Medicine  November 2013
3. Ronald et al. Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation August 2009