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Kosmas et al. Vessel Plus 2019;3:2 I http://dx.doi.org/10.20517/2574-1209.2018.79 Page 3 of 7

Systemic states, such as inflammation and its equivalent acute phase response (observed after surgery
and during infection or trauma), can induce significant changes on the HDL particle. During acute phase
response, pro-inflammatory cytokines promote changes in the structure of plasma proteins, including
those of the HDL particle. Interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor-α are released during
acute phase response and promote the synthesis of serum amyloid A (SAA) and group IIA secretory
phospholipase A2 (sPLA2-IIA), which act as pro-inflammatory molecules. SAA interacts with HDL
and may result in a faster clearance of the HDL particle, resulting in reduced HDL and ApoA-I plasma
levels. In addition, SAA promotes the loss of the anti-inflammatory activity of HDL and renders the HDL
particle pro-inflammatory [15-17] . With regard to sPLA2-IIA, its activation promotes the breakdown of HDL
phospholipids with subsequent accumulation of two proatherogenic and pro-inflammatory lipid products,
[19]
[18]
lysophospholipids and fatty acids , which can also disrupt HDL protein structure .
Furthermore, in pro-inflammatory states, Apo-AI becomes a substrate for myeloperoxidase (MPO), a protein
released by macrophages, monocytes and neutrophils, which catalyzes the chlorination or nitration of
tyrosyl residues of ApoA-I molecules in HDL. MPO promotes oxidative damage of the HDL particle, which
[20]
leads to a significant reduction of its anti-inflammatory properties, thus rendering HDL dysfunctional .
Oxidized LDL is a powerful inducer of atherogenesis due to its role in endothelial dysfunction and foam
cell formation. The mechanism by which oxidized LDL promotes atherogenesis involves the promotion of
[21]
monocyte adhesion to the endothelium via activation of macrophages and mast cells . As it was alluded
to earlier in this review, under normal conditions, HDL has antioxidant properties and prevents oxidation
of LDL, which contribute to its cardioprotective effect. However, in pro-inflammatory environments, HDL
may also lose its ability to inhibit monocyte migration within the arterial wall and thus lose its antioxidative
effects on LDL particles [22,23] .

Another factor that can modify the antiatherogenic properties of HDL is the alteration in the HDL lipid
composition. Reorganization of HDL lipid components due to an upregulation of the activity of CE
transfer protein, as observed in insulin resistance states, such as the metabolic syndrome, can modify the
CE/triacylglyceride (TAG) ratio in HDL, which plays a crucial role for the antioxidant activity of HDL.
Furthermore, increased TAG content in the lipid core may also cause dysregulation of CE transfer through
[24]
scavenger receptor class B type I, therefore impairing RCT .

It has been also shown that certain disease states may impair HDL function. Disorders such as
atherosclerosis and type 2 diabetes mellitus promote a subclinical chronic inflammatory microenvironment
at a biomolecular level, eliciting protein remodeling of HDL with subsequent disruption of its anti-
atherogenic, antioxidative and anti-inflammatory properties [25,26] . Furthermore, ApoA-I glycation impairs
[27]
[29]
[28]
HDL functionality , leading to the impairment of the anti-atherogenic and anti-inflammatory
properties of HDL.
Environmental factors have also a significant impact on HDL function. Factors that alter HDL functionality
include smoking, obesity and dietary habits. HDL is susceptible to oxidative modifications by cigarette
[30]
smoking. As a result, HDL loses its atheroprotective properties in smokers and becomes dysfunctional .
[31]
With regard to obesity, there is evidence that it may reduce CEC and impair HDL functionality . In
addition, consumption of saturated fat has been shown to impair arterial endothelial function and reduce
the anti-inflammatory activity of HDL. On the contrary, the anti-inflammatory activity of HDL is enhanced
[32]
after consumption of polyunsaturated fat .

IMPACT OF DYSFUNCTIONAL HDL ON CVD
There is extensive evidence from clinical studies confirming the adverse role of dysfunctional HDL on
atherogenesis and the risk for CVD.