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Review Article

Atherosclerosis: Current perspectives

Abha Pandit a,*, Abhay Kumar Pandey b


a
Department of Medicine, Index Medical College Hospital and Research Centre, Indore, MP, India
b
Department of Physiology, All India Institute of Medical Sciences, Bhopal, India

article info abstract

Article history: Atherosclerosis is among greatest concerns of contemporary medical science and care, and
Received 14 March 2015 its dangerous sequel are common knowledge. Atherosclerosis is not just state of excessive
Accepted 9 April 2015 activation of innate but involvement also of adaptive immune responses. Adipose tissue
Available online xxx cytokines and their diverse shared biological traits with the immune system counterparts
orchestrate an immune mediated inflammatory process. Medical progress in transcript-
Keywords: omics and epi-genetics has primarily been driven in recent years by the subclinical
Atherosclerosis chronic inflammation implied in atherosclerosis. Contemporary evidence based medicine
Thromboembolism has added obligation to individualized address implying molecular approach to diagnosis
Chronic inflammation and management. The context of new knowledge on pathogenesis and rational remedia-
Endothelial dysfunction tion is pertinent to update clinical approach to atherosclerosis and its complications. The
present narrative attempts to incorporate some current perspects for discussion.
Copyright 2015, Indraprastha Medical Corporation Ltd. All rights reserved.

contribution to chronic diseases as atherosclerosis, diabetes


1. Introduction and cancer.2

A century ago in 1914, Anitchkow explained role of cholesterol


in development of atherosclerosis and gave cholesterol fed
rabbit model of atherosclerosis. Atherosclerosis is a complex, 1.1. Epigenetics perspective
partly physiological phenomenon that commences in early
childhood. The growth and localization of individual plaque The perturbations in cellular function may be mediated by
determines its pathological significance. Endothelial epigenetic mechanisms.3 Diet, smoking, physical activity and
dysfunction, vascular smooth muscle cell proliferation/inva- other environmental exposures alter epigenetic marks and
sion/secretion, matrix fragmentation, collagenization and processes. Nutrition and lifestyle factors impact upon major
glycation are characteristics of aging arterial phenotype that cellular stressors, e.g. inflammation, metabolic stress and
creates a microenvironment enriched with reactive oxygen oxidative stress. Opportunities for developing novel in-
species (ROS) for pathogenesis of arterial disease. This nich terventions to prevent, delay or treat the complex diseases
creates an age associated arterial secretory phenotype.1 can emerge from epigenetic understanding. As an example,
Chronic stresses which require significant cell renewal, genome-wide analysis of DNA methylation marks (which vary
frequently disturb tissue homeostasis, with causal between individuals and within individual over a substantial

* Corresponding author.
E-mail address: drabhaindore@gmail.com (A. Pandit).
http://dx.doi.org/10.1016/j.apme.2015.04.002
0976-0016/Copyright 2015, Indraprastha Medical Corporation Ltd. All rights reserved.

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dx.doi.org/10.1016/j.apme.2015.04.002
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time period) has revealed genetic loci which are associated background. Diet can have long lasting effect on PPARa gene
with adiposity.4 expression and parental exposures may induce unique
Different rates of chronic disease afflictions in different epigenetic effects that underlie complex disease.19
ethnic groups have genetic bases. The same is important also
to explain very high chronic disease prevalence in society. The
implied genes may have been useful in earlier stages of evo- 2. Pathogenesis
lution that drastically differ from present. Genes which allow
the fetus to successfully adapt to under-nutrition are likely to Atherosclerotic process is preceded by endothelial inflam-
be favored by natural selection, even though they may lead to mation provoked by atherogenic risk factors and begins with
disease and premature death in later life.5 It is alarming that uptake of modified LDL-cholesterol at certain sites. Smooth
proportion of obese women getting pregnant is consistently muscle proliferation and formation of extracellular matrix
on rise and obesity associates deleterious consequences to around the developing fatty deposit, leads to atheroma or
baby.6,7 Over-nutrition associates stress in utero and may atherosclerotic patch. Such plaque is prone to break away and
epigenetically mark the developing fetus, with long term trigger thromboembolism and clinical manifestations.
consequences for patterns of gene expression, cell function
and health. The genes involved in regulating appetite and 2.1. Involvement of immune mechanisms
satiety are differently regulated, a mechanism potentially
risky for promoting obesity.8 While most epi-genetics Atherosclerosis is chronic inflammatory process associated
research is currently devoted to fetal and early postnatal life, with enhanced serum levels of inflammation parameters,
the possibility of lifelong epi-genome plasticity in response to including C-reactive protein in particular. As seen in chronic
dietary or other exposures needs examination. inflammation, atherosclerotic vessels produce hydrolytic en-
zymes, adhesion molecules, cytokines and growth factors.
1.2. Perspective on master metabolic switch, the PPARs The patho-physiology of atherosclerosis comprises of various
important steps. These include, enhanced endothelial
PPAR nuclear receptor superfamily has three isoforms alfa permeability, expression of adhesion molecules, monocyte
(PPARa), beta/delta (PPARb), and gamma (PPARr), playing immigration and adhesion, foam cell formation and fatty
important role in regulation of metabolism of carbohydrates, streaks.
lipids and protein. Effective strategies aiming at prevention Health and disease homeostasis depends largely upon the
and elaboration of therapeutic actions on obesity, diabetes recognition and response to damage associated molecular
and its complications may be based on PPAR mechanisms of patterns (DAMPs) derived endogenously, or the exogenous
metabolic regulation. PPARb was seen to regulate expression pathogen associated molecular patterns (PAMPs). In the
of genes for proteins involved in uptake and storage of fatty maintenance task appropriate innate and adaptive immune
acids and retinol.9 Vitamin A deficiency was found to increase responses, degree of inflammation and sets of mediators, are
PPAR expression and modified the regulation of expression of implicated. Increasing numbers of endogenous host origin
genes for enzymes regulating mitochondrial energetic.10 danger signals are being identified, including the oxidized-
Study in rat showed vitamin A and E regulate gene expres- modified LDL. Increased lipid per-oxidation in the vessel
sion of carbohydrate and lipid metabolism and also amelio- endothelium generates oxidation specific epitopes. These
rate changes associated with obesity induced by high fat epitopes on oxidized lipoproteins and on the surface of dying
diet.11 cells and circulating micro-particles, have potential to react
Evidence of involvement of nuclear peroxisome pro- with germline encoded pattern recognition receptors (PRRs)
liferator activated receptors is found in pathogenesis of present on both immune and nonimmune cells. Robust pro-
chronic diseases stemming from metabolic disorder.12e16 inflammatory and pro-thrombotic responses may be then
Environmental factors as diet interact with genetic back- triggered.20
ground to modulate metabolic promoters and this relation- TLRs (Toll Like Receptors, the molecular pattern recog-
ship is affected by polymorphism in PPAR-alfa (PPARa). The nizing receptors) are important for development of athero-
Relationships between polyunsaturated fatty acid (PUFA) sclerosis and are expressed in atherosclerotic lesions.21
intake and lipid parameters exhibit differences among ethnic Oxidized LDL up-regulates TLR expression in macrophages.
groups by effect of PPARa genetic variants. Influence of allele TLR-NFkB pathway is activated in the lesions, transcripting
frequencies of PPARa SNPs (single nucleotide polymorphisms) genes related to inflammation and cell proliferation, critical to
on genotypeediet interactions was thus, indicated in relation atherogenesis.22 These ultimately lead to synthesis and
of n6 or n3 fatty acid intake and total and LDL serum choles- release of antimicrobial peptides and inflammatory cytokines
terol concentration.17 Other PPAR-gamma (PPARr) and PPARa that provide critical link to adaptive immune response.23 Pro-
genotype interactions have also been described, in reference inflammatory cytokines with Th1 type cytokine Interferon-
to relation of dietary intakes with plasma lipids.18 PPARa is gamma (IFNr), being a key mediator, play major role and a
involved in homeostasis of lipids in the fasted as well as systemic chronic low grade immune mediated inflammation
postprandial state of fat rich diet. Lifestyle, drugs and dietary (scLGI) is recognized to culminate in to atherosclerosis.
modifications, including consumption of foods that can acti- Cascades of systemic inflammatory mediators activating
vate PPARa can affect its metabolic responses. The genetic the endothelium have cytokines, such as IL1 and TNF-alfa as
variant determines specificity of these effects. Disease risk proximal components. These lead to endothelial dysfunction
associating the variants depends on such interaction and alter the balance within lymphocyte subpopulations. The

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later contain distinct arsenals of secretory mediators, such as secretion of local growth factors by macrophages. Stromal cell
interferons, interleukins and chemokines. Lymphocyte sub- proliferation and extracellular matrix remodeling is added by
types Th1 and Th17 are proinflammatory. TNF-alfa is pivotal neo-vascularisation (angiogenesis) within the evolving gran-
cytokine in the inflammatory cascade and is directly involved uloma or future plaques.34
in vascular patho-physiology.24 There are regulatory anti-
inflammatory opponents, the Treg and Th2 cells.25 Specific
2.3. Role of the oxidant stress
negative regulators and regulating pathways maintain im-
mune homeostasis and dampen injurious extension, while
Vast array of extracellular harmful signals both internal
allowing efficient elimination of infection and facilitate repair.
(hyperglycaemia, dyslipidaemia, inflammatory stimuli) and
In obese persons, the peri-vascular adipose tissue adds to
environmental (UV light, microbial toxins, chemicals, ciga-
inflammation within surrounded vessels by secreting
rette smoke) induce nitroxidative stress in cells. The associ-
atherogenic cytokines.26 Macrophages infiltrating visceral fat
ated molecular damage is considered as common intracellular
differ in behavior from those in peripheral subcutaneous fat.
pathway leading to several metabolic disorders.37,38 When the
Important pro-inflammatory cytokines viz. tumor necrosis
extracellular stimuli are translated in to intracellular damage
factor alpha (TNF e alpha) and interleukin-6 (IL-6), are liber-
due to free radicals, several transcription factors are activated
ated by macrophages of visceral fat. Increased production of
to deal with non steady state conditions. A redox sensitive
the proinflammatory adipokine Leptin in scLGI with IFNr and
transcription factor NFkB activation mediates transcription of
Interleukin-6 (IL6) combination represents a link between
a large number of pro-inflammatory gene families, including
obesity, atherosclerosis and cardiovascular diseases. Leptin
cytokines, chemokines, adhesion molecules, inflammatory
also contributes immunity shifting to Th1 type, with decrease
enzymes etc.39 Cytokines and their protein products, all cause
in tryptophan levels along increased abdominal obesity.
activation of NFkB pathway.40
Enzymatic degradation by activated macrophages of abdom-
Excess of reactive oxygen species (ROS), not neutralized by
inal fat bring this about.27 Very little adiponectin is released
antioxidant defense, attack tissues and molecules. The ROS
from cells of visceral fat/macrophage complex. The cytokines
modulate cell movements, growth and apoptosis (death) as
cause insulin resistance, endothelial dysfunction and
well as turnover of extracellular matrix in deleterious mode
atherogenesis.28
contributing to atherogenesis.41 There are two strongly
Key role of inflammation is suggested as a link between
atherogenic consequences. Lipoprotein are oxidized to form
risk factors for atherosclerosis and its complications Syner-
oxLDL. Nitric oxide produced by endothelium is depleted by
gistic effects of hyper-cholestreamea and infection are indi-
conversion to toxic peroxynitrite radical, combining with su-
cated in accelerating atherosclerosis. Aerobic infection of
peroxide anions. The atherogenic LDL modifications form
vascular endothelium may be implicated in atherogenesis and
self associates that bypass the receptor regulated pathway
even consequent coronary syndromes. DNA of microbes like
and enhance intracellular lipid accumulation. Modified LDL is
Chlamydia pneumonia, Helicobacter pylori, Herpes virus have
highly oxidizable which is the ultimate of multiple modifica-
been detected in human atheroma.29 In addition periodontal
tions. In all likelihood, LDL oxidation occurs intracellularly, as
disease is found to correlate with markers of atherosclerosis
oxidized LDL is not detectable in blood, only auto-antibodies
and inflammation.30 Experimental studies have demonstrated
against malondialdehyde-modified LDL are found in circula-
that an inflammatory subset of monocytes/macrophages
tion. The ox-LDL-IgG auto-antibodies may interact with nave
preferentially accumulate in atherosclerotic plaque and pro-
LDL triggering formation of highly atherogenic complexes,
duce pro-inflammatory cytokines.
binding complement component C1q and fibronectin. Auto-
antibodies and immune complexes are important contribu-
2.2. Role of modified LDL-cholesterol
tors to atherogenicity.31

Modified low density lipoproteins and auto-antibodies against


them contribute to atherogenicity, which refers to accumu- 2.4. Role of hyperglycemia & insulin resistance
lation of lipid within vascular intima, triggering cellular
atherogenesis.31 Blood of the atherosclerotic patients contains Hyperglycemia in the diabetics upregulates NADPH oxidase
three types of atherogenic modified LDL, i.e. small dense, and promotes generation of reactive oxygen species in car-
electronegative and disialylated LDLs.32,33 Oxidized LDL diovascular cells, and also endothelial dysfunction in coro-
(oxLDL) is a potent chemo-tractant for inflammatory cells, naries.42 Insulin is physiologic stimulus for NO production by
especially monocytes and some lymphocytes.34 Binding of vascular endothelium.43 Deficient NO production constitutes
oxLDL and production of chemotectic MCP-1 lead the endothelial dysfunction.44 Insulin resistance crucially de-
inflammation events in vascular endothelium. The lectin like ranges endothelial biology. In the presence of hyperglycaemia
oxLDL receptor-1 (LOX-1), is up-regulated on endothelium in type2 diabetes, LDL undergoes glycoxidative modification
accompanied with increase in blood pressure.35 When lots of promoting atherosclerosis. The glycoxLDL promotes greater
oxLDL is loaded in cells, they turn into foam cells. Macro- aldosterone release compared to native LDL, from
phages accumulating in vascular intima cause fatty streak angiotensin-II sensitized cells. Modified LDL evocks aldoste-
rich with foam cells.36 Such cells express more scavenger re- rone release mediated by transcriptional regulation of aldo-
ceptor for more uptake of oxLDL and their mobility is inhibited sterone synthase and cAMP dependant Protein KinaseA. The
resulting in local stay and atherogenesis. oxLDL also acts as reactions involve phosphorylation of ERK1/2 and
mitogen for smooth muscle cells and macrophages. There is janusKinase2.45

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Macrophage behaviors, e.g. proliferation, adhesion, the process of atherogenesis at those sites. A monocyte che-
migration and TNFr synthesis are increased by exposure to motractant protein (MCP-1) causes accumulation of mono-
high glucose. Glucose is shown to increase RhoA Kinase cytes in vascular intima and their transformation into
(ROCK) activity in macrophages and activates them. ROCK macrophages is crucial to pathogenesis of atheromas.55 There
activity is critical to hyperglycaemia-enhanced adhesion and is macrophage activation with release of mediators for
TNFr production. Macrophages activated mainly through smooth muscle hyperplasia and raised extracellular matrix
ROCK/JNK and ROCK/BKK pathways acquire a more pro- especially collagen type I.56
inflammatory phenotype, eventually contributing to athero- Atherogenic plaque development involves multiple extra
sclerosis.46 Platelet aggregates with inflammatory cells are and intracellular signals, engaging cells from the immune
seen in diseased coronary vessels. Such interaction contrib- system and from vasculature. Cross talk among atheroma
utes to inflammation, endothelial dysfunction as well as interacting cell types is seen to occur leading to increased
atherogenesis.47 Diabetic patients exhibit higher fraction of P- activation of Signal Transducer and Activator of Tran-
selectin positive platelets in circulation. This finding corre- scriptome1 (STAT1) and elevated expression of proin-
lates significantly with carotid atherosclerosis. flammatory mediators.57 IFNr and TLR4 are the key factors
contributing to every stage of plaque development. STAT1
2.5. Role of hypertension dependant differential integration of signals between IFNr
and TLR4 in vascular cells and atheroma interacting immune
Endothelial dysfunction denotes partial or complete loss of cells, results in increased leukocyte attraction, adhesion,
balance between vasoconstriction and vasodilatation; growth VSMC proliferation and migration, which are important fea-
promoting and inhibiting factors; proatherogenic and anti- tures of endothelial cell dysfunction and early triggers of
atherogenic factors and pro-coagulant and anticoagulant atherosclerosis.
factors. Increased activity of renin angiotensin and other
complex processes contribute to elevated blood pressure.
High blood pressure imposes hemodynamic disorder, favoring 4. Plaque rupture and clinical consequences
pathogenic events of atherogenesis.48 Overactive RAS system
would produce more angiotensin-II, causing blood pressure In advanced atherosclerosis, ox-LDL by its cytotoxic effect
elevation. Additionally, generation of reactive oxygen species causes apoptosis of surrounding cells leading to plaque
is increased resulting in oxidative stress. Oxidative stress ac- rupture. This may activate pro-coagulant pathways via
tivates ubiquitous transcription factor Nuclear factor kappa-B platelet aggregation and thrombotic consequence. Evolution
(NFkB), leading to expression of inflammatory cytokines and of atherosclerotic lesion towards complications involves
consequent endothelial dysfunction. There is also more repeated intra plaque haemorrhages (IPH). IPH is main deter-
fibroblast proliferation and matrix formation, implicated in minant of plaque evolution toward rupture. Inward sprouting
making of atherosclerotic plaque.48 of neo-angiogenesis from adventitia toward the plaque across
The increased shear stress on vascular endothelium, media is one source of IPH in the plaque. This is initiated by
upregulates expression of endothelial adhesion molecules lipid mediators generated by the plaque on luminal side and
and various cytokines and growth factors. There is increased convicted to smooth muscle cells. In response, the PPAR-
expression of heparin sulfate proteoglycan in vascular endo- gamma receptors on the vascular smooth muscle cells are
thelium which binds the apoprotien in LDL and increases stimulated leading to increased expression of VEGF (vascular
oxidative modification of LDL cholesterol. Pre-hypertension endothelial growth factor), responsible for neo-angiogenesis.
refers to blood pressure profiles in range of 120e139 mm Hg The neo-vessels are highly susceptible to leakage. RBCs are
systolic and 80e89 mm Hg diastolic. Pre-hypertension has the main cells in IPH bearing hemoglobin and membrane rich
greater risk of developing hypertension,49 and itself carries in unesterified cholesterol. These participate in oxygen free
increased cardiovascular events risk independent of other radical production as well as cholesterol accumulation. Pres-
factors.50 The hypertensive patients exhibit higher levels of ence of iron, glycoprotein A and ceroids in IPH also make that
dyslipidaemia.51e54 focus for white cell attraction and probable infection.58 The
macrophages secrete enzymes as collagenase, gelatinase,
cathepsin etc. These degrade matrix and cause desquamation
3. Formation of atheromatous plaques of endothelial cells. Atherosclerotic plaques having thin
fibrous cap with high inflammation and increased proteases
In microvasculature, decreased blood flow increases shear including metallo-proteinases (MMPs) are vulnerable to
stress which results in decrease of NO production. Inhibitory rupture. Initiation of breakdown of collagen cap requires
control of NO on NFkB activity is therefore lost. This results in interstitial collagenases, a subfamily of MMP-1, 8 and 13.
increased transcription of genes for inflammatory products. Among these, MMP8 is most important to rupture and is
Activation of NFkB in microvasculature and TGF-beta (trans- derived from leukocytes infiltrating the plaque as part of
forming growth factor beta) pathway causes induction of inflammation. The fibrous collagen cap is produced by arterial
several inflammatory cytokines oxLDL, C-reactive proteins. smooth muscle cells.59 Plaque rupture exposes basement
Deficiency of NO causes vessel smooth muscle contraction, collagen, triggering platelet aggregation and thrombotic con-
cellular proliferation, platelet activation, increased adhesion sequences e.g. acute coronary syndrome.60 Matrix
molecule expression etc. Critical change in shear stress at metalloproteinase-14 in the plaque increase vulnerability to
points of vascular bifurcations and bends appears to initiate rupture. Over-expression of tissue inhibitor of

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metalloproteinase-3 (TIMP3) is protective against plaque of omega3 fatty acids and their relation to antioxidant ca-
rupture. The more foamy macrophages are rich with MMP-14 pacity is amply reported. Even omega6 acids add such effects
while less foamy contain TIMP3.61 in certain contexts.79 Endogenous enzyme superoxide dis-
Immunological insight is also increasing. Balance of TH-17 mutase and glutathione peroxidase are antioxidant defense
(T helper 17) to T reg (T suppressor) lymphocytes is found components and modulate synthesis of cell signaling mole-
important in preventing progression of atherosclerotic plaque. cules that regulate oxidative stress.80 Dietary micronutrients,
Increased TH-17 with decreased Treg function leads finally to manganese, zinc, copper and selenium can act as cofactors for
acute coronary syndrome.62 Loss of matrix synthesizing endogenous enzymes, whose activity may be jaeopardized
smooth muscle cells would weaken and rupture the plaque. amid deficiency of these nutrients.81,82 There is lack of con-
Inflammation increases activated mast cells in plaque which sistency however, in reports of benefits of antioxidant sup-
secrete mediators such as heparin proteoglycans which inhibit plements. The descrepancies apparently emphasize
SMC proliferation and collagen synthetic activity. Chymase significance of attainable fine physiologic balance between
degrades extracellular matrix to disrupt and apoptose SMCs. ROS production and neutralization, at tissue level.
Mast cells are thus, participants in plaque rupture63 Safe and effective treatments for inflammatory diseases do
not currently exist, because most therapies either target a
single inflammatory mediator or broadly affect multiple body
5. Remediation considerations systems. First kind drugs work in very specific contexts. Sec-
ond type drugs cause unwanted side and adverse effects. Gene
Efforts to delay progression of atherosclerosis and its clinical specific control of TLR induced inflammatory response may
sequele aim at controling risk factors e.g. obesity, hyperten- help selective modulation of inflammation. Inhibitors of TLR
sion, diabetes, dyslipidaemia and infections (chronic). Resort signaling may control inflammation, but jaeopardise other
to platelet function inhibitory and vasorelaxing therapies are functions subserved by the TLR induced genes. Recent evi-
also relevant. Dietary and lifestyle measures to rid off obesity dence suggests that many inflammatory genes are regulated
are important. Surgical removal of excess visceral fat is rele- by epigenetic modification of individual promoters. Gene
vant but the quantitative impacts remain uncertain.28 Good specific control of functional subgroups of inflammatory
control of diabetes is most useful approach to improve genes is an emerging paradigm for modulation of innate im-
endothelial function. Statins (lipid lowering agents) and ACE mune responses, and developing novel agents for chronic
inhibitors (antihypertensive) possess welcome potentials for inflammatory diseases.83,84 Notwithstanding innovative sci-
correcting endothelial dysfunction.44 Anti-hypertensives with entific contemplations, prophylactic antiplatelet aspirin
peripheral vasodilatory effect particularly appear to improve therapy holds ground of rationality as well as efficacy.85
endothelial function.64 Newer novel beta adrenoceptor Chronic inflammatory endothelial dysfunction underlies
blockers impressively correct endothelial dysfunction.65 Sta- atherothrombotic disorders. Refined strategiess of addressing
tins have emerged as first line agents to delay progression of individual and synergic groups of risk factors for endothelium
atherosclerosis but the benefits exhibit marked individual biology remain at core of aspired advances.
variations.66 Situations of increased atherosclerosis risk
involve lipoperoxidation, viz smoking,67 Diabetes mellitus68
and the phenotype is characterized by small dense LDL.69 Conflicts of interest
There is no apparent benefit of anti-infective therapy in
stopping progression of atherosclerosis. All authors have none to declare.
Melatonin is currently of great research interest in context
of new anti atherosclerosis therapy. It regulates immune
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