Vulnerable Plaque: The Paradigm That Failed Feb. 2016
http://circres.ahajournals.org/content/119/9/972.full
Atherosclerosis,
the precursor to acute coronary syndromes, is a disease of chronic
inflammation triggered initially by the focal subendothelial retention
of apolipoprotein B100–containing lipoproteins and exacerbated by other
risk factors, such as smoking, diabetes mellitus, and hypertension.1,2
The persistence of these stimuli promotes a cycle of nonresolving
inflammation that promotes atherosclerotic lesion development and, most
importantly, progression to the unique types of necrotic plaques that
cause ACS. In order for inflammation to resolve, there must not only be
an abatement of initiating risk factors but also an initiation of
proresolving molecular and cellular pathways that act to restore tissue
homeostasis and promote repair. On the basis of the observations of
human and animal atherosclerotic plaque features, genetic and
therapy-based causation studies in mice, and cell culture studies with
macrophages, researchers over the past two decades have proposed that
defective resolution drives atherosclerosis progression. For example,
advanced atherosclerosis is characterized by failure to reduce plaque
inflammatory cell number, inefficiency in removing dying cells, and
suboptimal tissue repair. However, the molecular basis of defective
inflammation in atherosclerosis remained to be precisely defined.
Article, see p 1030
The
inflammation resolution program is carried out by several molecular and
cellular effectors. Among these are a superfamily of unsaturated fatty
acid–derived lipid mediators referred to as specialized proresolving
mediators or SPMs. SPMs are biosynthesized by inflammatory cells during
self-limited inflammation and, by interacting with specific cell-surface
receptors on immune cells and other cell types, trigger processes that
dampen inflammation and promote tissue repair. Moreover, exogenously
administered SPMs and other proresolving mediators have shown efficacy
in triggering resolution of several types of chronic diseases, including
atherosclerosis. Although characterized within human arterial cells in
the early 1990s by Brezinski et al,3 a comprehensive and direct cataloging of SPMs within atherosclerotic lesions is only now coming to light.
Implications for SPMs in Atherosclerosis
The
major types of SPMs are the lipoxins (LX), resolvins (Rv), protectins
(P), and maresins (MaR), each of which is endogenously biosynthesized in
resolving exudates and activates specific G-protein–coupled receptors.4
The precursors of SPMs include diet-derived polyunsaturated fatty acids
that are substrates for SPM biosynthetic enzymes, including
lipoxygenases and cyclooxygenases. Lipoxins are derived from omega-6
arachidonic acid, whereas resolvins, protectins, and maresins are
derived from omega-3 fatty acids, eicosapentaenoic acid, and
docosahexaenoic acid. In human plasma, low levels of SPMs are correlated
with peripheral and coronary artery disease.5
In mouse models of atherosclerosis, macrophage-specific overexpression
of 12/15-lipoxygenase (LOX), which increased the local biosynthesis of
LXA4, RvD1, and PD1, suppressed lesion development.6 In terms of human evidence, variants in the gene, ALOX5,
which can synthesize proresolving SPMs in the presence of n-3 fatty
acids but proinflammatory/proatherosclerotic leukotrienes in the
presence of n-6 fatty acids, was associated with decreased or increased
risk for subjects ingesting diets rich in n-3 versus n-6 fats,
respectively.7
Interestingly, the benefit of fish oils when analyzed in the absence of
genetic interactions has yielded conflicting results. In this setting
of active investigation, what remained unclear were the levels and
temporal patterns of lesional SPMs during atherosclerosis progression.
An Imbalance of Bioactive Lipids in Advanced Plaque
In a recent study in this issue of Circulation Research, Viola et al8
test the hypothesis that atherosclerosis progression is tied to a
deficit of arterial SPMs. The investigators performed aortic lipid
mediator profiling of advanced atherosclerotic lesions from fat-fed
hyperlipidemic mice after carefully snap-freezing aortas and utilizing
liquid chromatography in tandem with mass spectrometry. Their findings
indicate that the levels of the inflammatory lipids leukotriene B4 and
prostaglandin E2 increase as atherosclerotic plaques mature. Conversely,
advanced plaques had significantly lower levels of 2 types of SPMs,
RvD2, and Mar1. Importantly, these SPMs declined progressively with
longer duration of fat feeding. Of note, RvD1, LXA4, and
protectins were below detection limits. Thus, atheroprogression was
associated with an increasing and unbalanced ratio of inflammatory
versus resolving bioactive lipids in plaques.
In humans,
lesions that are unstable and at risk for rupture are so-called
vulnerable. Vulnerable plaques are marked, in part, by thin fibrous caps
and increased cellular and macrophage death, the effects of which are
compounded by defects in dead cell clearance, or efferocytosis. Taking
into account these features of unstable plaques, Viola et al8
generated an index of plaque instability and found that increases in
leukotriene B4 and prostaglandin E2 positively correlated with this
index. In contrast, RvD2 and MaR1 levels correlated with opposing
indices of plaque stability, including the aggregate of smooth muscle
cell number, the surface area of collagen deposition, and fibrous cap
thickness.
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