Atherosclerosis 251 (2016) 525e527

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Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Discussion

HDL metrics, let’s call the number thing off?

Andrei C. Sposito
Laboratory of Atherosclerosis and Vascular Biology (AtheroLab) Cardiology Department, State University of Campinas (UNICAMP), State University of
Campinas School of Medicine, Campinas, Sa ~o Paulo, Brazil

a r t i c l e i n f o

Article history:
Received 19 June 2016
Received in revised form
24 June 2016
Accepted 28 June 2016
Available online 5 July 2016
Keywords:
HDL
Myocardial infarction
Function
High-density lipoprotein (HDL) can be defined as an endoge-
nous nanoparticle capable of mediating a wide range of actions
through different molecular pathways, involving different cells and
several systems. Its composition includes a substantial and highly
variable number of proteins, hydrophilic and hydrophobic lipids,
and several microRNAs [1]. Some of HDL’s biological actions include
immuno-inflammatory and oxidative stress attenuation, endoge-
nous lipid transfer, and anti-thrombotic, anti-apoptotic and endo-
thelial function modulation. Due to this set of actions, HDL has been
perceived as having the ability to prevent atherogenesis [2].
Nevertheless, considering the presence of HDL in multiple
atherosclerosis-free species, we can infer that for thousands of
years this lipoprotein has at least somewhat contributed to survival
in a broader manner and, hence, it was conserved across diverse
species and over time.
Recent data from both basic and clinical science has emerged
the concept that the effective antiatherogenic action of HDL relies
not only on its plasma concentration but rather on combinations of
particle features and activity of proteins localized at cell mem-
branes, such as scavenger receptor class B member 1 [3] and ATP-
binding cassette, sub-families A1 [4] and G1 [5], or in the cytosol,
such as sphingosine kinase-1 and sphingosine-1-phosphate lyase
[6] - for each of the HDL’s protective actions there are ideal
DOI of original article: http://dx.doi.org/10.1016/j.atherosclerosis.2016.06.037.
E-mail address: andreisposito@gmail.com.
combinations of cell and lipoprotein phenotypes. Thus, the adap-
tation of the limited pool of HDL particles in the bloodstream to face
distinct clinical needs through its large spectrum of mechanisms is
only possible due to a two-way, continuous intravascular remod-
eling of HDL features. Under this current perspective, there is no
room for the old concept of HDL as a silver bullet, but rather as a
component of a complex, dynamic and continuously remodeled
system: the HDL system (Fig. 1).
In the current issue of Atherosclerosis, the article by Distelmaier
et al. [7] has focused on the antioxidant role of HDL during
myocardial infarction (MI). In addition, the authors show that this
effect is unrelated to particle plasma concentration but is influ-
enced by gender. The study has several interesting aspects, but in
particular, has two messages that should be taken home.
Firstly, HDL levels or functionality must be systematically
examined taking gender into account. The cellular uptake of free
cholesterol, for example, is best mediated by HDL particles bearing
greater diameter, high sphingomyelin content and lacking apoli-
poprotein A2. This very physical aspect of HDL is highly influenced
by the female gender as well as age and ethnicity e HDL particles
are usually larger and more efficient acceptors of cholesterol in
women than in men [8e10]. In contrast to efflux capacity, antiox-
idant and anti-inflammatory activities are better conducted by
small particles [11,12]. Thus, theoretically, the predominance of
large HDL particles in women should mean a greater proportion of
HDL’s role in the reverse cholesterol transport than in the attenu-
ation of oxidative stress injury; in men, the opposite would be
expected. The study of Distelmaier et al. [7] has shown that this is
not the case.
Besides the size of HDL, other peculiarities are related to gender
as the content of proteins or lipids, which may offset or even
overcome the apparent disadvantage in the predominance of large
particles. In women, for example, esterification of estradiol by
lecitina-colesterol aciltransferase expands HDL antioxidant capac-
ity via direct action of the esterified estradiol, inhibiting the gen-
eration of superoxide, hydrogen peroxide and hydroxyl radicals
[13,14]. Hence, there are qualitative features to HDL particles in
women, which may simultaneously favor both cholesterol efflux
and antioxidant activity.
Yet, when interpreting studies in patients with MI, it must be
borne in mind the above-commented adaptability of HDL particles
to different clinical conditions. Possibly due to biological advantage

http://dx.doi.org/10.1016/j.atherosclerosis.2016.06.044
0021-9150/© 2016 Elsevier Ireland Ltd. All rights reserved.
526 A.C. Sposito / Atherosclerosis 251 (2016) 525e527

Fig. 1. The HDL system. The interaction of HDL with cholesteryl transfer ester protein (CETP), hepatic lipase (HL) and endothelial lipase (EL) as well as the transfer of its cholesteryl
ester (EC) content to the hepatocytes via the scavenger receptor class BI (SR-BI) favor the formation of smaller particles carrying greater antioxidant and anti-inflammatory activities.
The free cholesterol (CL) and phospholipid (PL) transfer and the action of Lecithin-cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP), on the other hand,
favor the transformation of HDL into larger particles. These larger HDL are more suited to the reverse cholesterol transport, anti-thrombotic and anti-apoptotic actions and even the
vasomotor modulation via activation of endothelial nitric oxide synthase (eNOS). From the cell point of view, the activity of membrane proteins such as ATP-binding cassette
transporters (ABC) A1, G1, C1 and G2, sphingosine-1-phosphate transporter (SPNS2) and SR-BI are key to regulate not only the HDL phenotype but equally its beneficial effects.
Likewise, cytosol proteins as sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate lyase (S1P lyase), regulate sphingosine-1-phosphate (S1P) bioavailability and inside-out
signaling via S1P receptors (S1Pr), which is important for the HDL mediated attenuation of apoptosis and ischemia-reperfusion injury.

of smaller particles in their antioxidant activity, in the acute phase
of MI there is a reduction in HDL size conditioned at least in part by
the increasing in the activity of cholesteryl ester transfer protein
[15,16]. Accordingly, this reduction of the average diameter of HDL
generates particles with the greatest potential for antioxidant ac-
tion [15]. Thus, the functional performance of HDL during the acute
phase of MI is hardly predictable by functional or structural analysis
obtained during clinically stable conditions.
A second key aspect to consider from the findings of Distelmaier
et al. [7] relates to the existence of a dynamic interaction between
oxidative stress and HDL during the acute phase of MI. As com-
mented above, HDL remodeling during MI attenuates cholesterol
efflux capacity but favors antioxidant activity, which can be bene-
ficial in mitigating myocardial and endothelial damage. Indeed, this
antioxidant activity is directly related to the residual endothelial
function after MI [15]. The increased availability of HDL during MI e
either by gene therapy in an in vivo animal model or by direct
coronary reperfusion using HDL-enriched solution in an ex-vivo
model e reduces MI size and improves left ventricular systolic and
diastolic functions [17e19]. Thus, the antioxidant capacity of HDL at
the moment of ischemia/reperfusion injury and particle remodel-
ing during the first days after this event may have substantial
importance. In addition, HDL’s potential role during MI may persist
after reperfusion through its action on endothelial cells and
platelets [20]. In fact, the oxidation of HDL increases its ability to
inhibit platelet aggregation, which is especially relevant after MI
[21]. In sum, data on HDL system obtained from models or in-
dividuals in stable conditions must necessarily be considered apart
from those obtained in acute inflammatory conditions.
Among humans, HDL’s operating spectrum was, for a very long
time, conditioned on a mean survival of up to 30 years of age. In
modern man, however, the long-lasting survival, the endurance to
acute oxidative/inflammatory events and the emergence of chronic
inflammatory stimulus presented a new challenge to the protective
role of HDL and even generated the possibility of a pathogenic role.
By a slight resemblance with low-density lipoprotein (LDL), HDL
has been envisioned in an oversimplified manner. Under this
analogy, negative results in prospective randomized trials have
aroused the feeling that the HDL’s lifeline ended when in fact it has
not yet even begun [22e25]. So far, despite a large body of evidence
indicates that several HDL actions can promote longevity, predict-
ing longevity from evaluations of this complex system remains
intangible. The findings of Distelmaier et al. [7] corroborate this
assumption. The only thing that is certain is that no one can ever
again estimate the protective role of HDL only by its plasma con-
centrations. The time has come to call the number thing off.
Conflict of interest
The author declared he does not have anything to disclose
regarding conflict of interest with respect to this manuscript.
Acknowledgements
A.C. Sposito is recipient of the Research Career Awards from the
National Council for Scientific and Technological Development
(CNPq, Brasilia, Brazil).
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