a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e7

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

Please cite this article in press as: Pandit A, Pandey AK, Atherosclerosis: Current perspectives, Apollo Medicine (2015), http://
dx.doi.org/10.1016/j.apme.2015.04.002
2 a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e7
time period) has revealed genetic loci which are associated
with adiposity.4
Different rates of chronic disease afflictions in different
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-
lution that drastically differ from present. Genes which allow
the fetus to successfully adapt to under-nutrition are likely to
be favored by natural selection, even though they may lead to
disease and premature death in later life.5 It is alarming that
proportion of obese women getting pregnant is consistently
on rise and obesity associates deleterious consequences to
baby.6,7 Over-nutrition associates stress in utero and may
epigenetically mark the developing fetus, with long term
consequences for patterns of gene expression, cell function
and health. The genes involved in regulating appetite and
satiety are differently regulated, a mechanism potentially
risky for promoting obesity.8 While most epi-genetics
research is currently devoted to fetal and early postnatal life,
the possibility of lifelong epi-genome plasticity in response to
dietary or other exposures needs examination.
1.2. Perspective on master metabolic switch, the PPARs
PPAR nuclear receptor superfamily has three isoforms alfa
(PPARa), beta/delta (PPARb), and gamma (PPARr), playing
important role in regulation of metabolism of carbohydrates,
lipids and protein. Effective strategies aiming at prevention
and elaboration of therapeutic actions on obesity, diabetes
and its complications may be based on PPAR mechanisms of
metabolic regulation. PPARb was seen to regulate expression
of genes for proteins involved in uptake and storage of fatty
acids and retinol.9 Vitamin A deficiency was found to increase
PPAR expression and modified the regulation of expression of
genes for enzymes regulating mitochondrial energetic.10
Study in rat showed vitamin A and E regulate gene expres-
sion of carbohydrate and lipid metabolism and also amelio-
rate changes associated with obesity induced by high fat
diet.11
Evidence of involvement of nuclear peroxisome pro-
liferator activated receptors is found in pathogenesis of
chronic diseases stemming from metabolic disorder.12e16
Environmental factors as diet interact with genetic back-
ground to modulate metabolic promoters and this relation-
ship is affected by polymorphism in PPAR-alfa (PPARa). The
Relationships between polyunsaturated fatty acid (PUFA)
intake and lipid parameters exhibit differences among ethnic
groups by effect of PPARa genetic variants. Influence of allele
frequencies of PPARa SNPs (single nucleotide polymorphisms)
on genotypeediet interactions was thus, indicated in relation
of n6 or n3 fatty acid intake and total and LDL serum choles-
terol concentration.17 Other PPAR-gamma (PPARr) and PPARa
genotype interactions have also been described, in reference
to relation of dietary intakes with plasma lipids.18 PPARa is
involved in homeostasis of lipids in the fasted as well as
postprandial state of fat rich diet. Lifestyle, drugs and dietary
modifications, including consumption of foods that can acti-
vate PPARa can affect its metabolic responses. The genetic
variant determines specificity of these effects. Disease risk
associating the variants depends on such interaction
Please cite this article in press as: Pandit A, Pandey AK, Atherosclerosis: Current perspectives, Apollo Medicine (2015), http://
dx.doi.org/10.1016/j.apme.2015.04.002
background. Diet can have long lasting effect on PPARa gene
expression and parental exposures may induce unique
epigenetic effects that underlie complex disease.19
2. Pathogenesis
Atherosclerotic process is preceded by endothelial inflam-
mation provoked by atherogenic risk factors and begins with
uptake of modified LDL-cholesterol at certain sites. Smooth
muscle proliferation and formation of extracellular matrix
around the developing fatty deposit, leads to atheroma or
atherosclerotic patch. Such plaque is prone to break away and
trigger thromboembolism and clinical manifestations.
2.1. Involvement of immune mechanisms
Atherosclerosis is chronic inflammatory process associated
with enhanced serum levels of inflammation parameters,
including C-reactive protein in particular. As seen in chronic
inflammation, atherosclerotic vessels produce hydrolytic en-
zymes, adhesion molecules, cytokines and growth factors.
The patho-physiology of atherosclerosis comprises of various
important steps. These include, enhanced endothelial
permeability, expression of adhesion molecules, monocyte
immigration and adhesion, foam cell formation and fatty
streaks.
Health and disease homeostasis depends largely upon the
recognition and response to damage associated molecular
patterns (DAMPs) derived endogenously, or the exogenous
pathogen associated molecular patterns (PAMPs). In the
maintenance task appropriate innate and adaptive immune
responses, degree of inflammation and sets of mediators, are
implicated. Increasing numbers of endogenous host origin
danger signals are being identified, including the oxidized-
modified LDL. Increased lipid per-oxidation in the vessel
endothelium generates oxidation specific epitopes. These
epitopes on oxidized lipoproteins and on the surface of dying
cells and circulating micro-particles, have potential to react
with germline encoded pattern recognition receptors (PRRs)
present on both immune and nonimmune cells. Robust pro-
inflammatory and pro-thrombotic responses may be then
triggered.20
TLRs (Toll Like Receptors, the molecular pattern recog-
nizing receptors) are important for development of athero-
sclerosis and are expressed in atherosclerotic lesions.21
Oxidized LDL up-regulates TLR expression in macrophages.
TLR-NFkB pathway is activated in the lesions, transcripting
genes related to inflammation and cell proliferation, critical to
atherogenesis.22 These ultimately lead to synthesis and
release of antimicrobial peptides and inflammatory cytokines
that provide critical link to adaptive immune response.23 Pro-
inflammatory cytokines with Th1 type cytokine Interferon-
gamma (IFNr), being a key mediator, play major role and a
systemic chronic low grade immune mediated inflammation
(scLGI) is recognized to culminate in to atherosclerosis.
Cascades of systemic inflammatory mediators activating
the endothelium have cytokines, such as IL1 and TNF-alfa as
proximal components. These lead to endothelial dysfunction
and alter the balance within lymphocyte subpopulations. The
 a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e7 3

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

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dx.doi.org/10.1016/j.apme.2015.04.002
4 a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e7
Macrophage behaviors, e.g. proliferation, adhesion,
migration and TNFr synthesis are increased by exposure to
high glucose. Glucose is shown to increase RhoA Kinase
(ROCK) activity in macrophages and activates them. ROCK
activity is critical to hyperglycaemia-enhanced adhesion and
TNFr production. Macrophages activated mainly through
ROCK/JNK and ROCK/BKK pathways acquire a more pro-
inflammatory phenotype, eventually contributing to athero-
sclerosis.46 Platelet aggregates with inflammatory cells are
seen in diseased coronary vessels. Such interaction contrib-
utes to inflammation, endothelial dysfunction as well as
atherogenesis.47 Diabetic patients exhibit higher fraction of P-
selectin positive platelets in circulation. This finding corre-
lates significantly with carotid atherosclerosis.
2.5. Role of hypertension
Endothelial dysfunction denotes partial or complete loss of
balance between vasoconstriction and vasodilatation; growth
promoting and inhibiting factors; proatherogenic and anti-
atherogenic factors and pro-coagulant and anticoagulant
factors. Increased activity of renin angiotensin and other
complex processes contribute to elevated blood pressure.
High blood pressure imposes hemodynamic disorder, favoring
pathogenic events of atherogenesis.48 Overactive RAS system
would produce more angiotensin-II, causing blood pressure
elevation. Additionally, generation of reactive oxygen species
is increased resulting in oxidative stress. Oxidative stress ac-
tivates ubiquitous transcription factor Nuclear factor kappa-B
(NFkB), leading to expression of inflammatory cytokines and
consequent endothelial dysfunction. There is also more
fibroblast proliferation and matrix formation, implicated in
making of atherosclerotic plaque.48
The increased shear stress on vascular endothelium,
upregulates expression of endothelial adhesion molecules
and various cytokines and growth factors. There is increased
expression of heparin sulfate proteoglycan in vascular endo-
thelium which binds the apoprotien in LDL and increases
oxidative modification of LDL cholesterol. Pre-hypertension
refers to blood pressure profiles in range of 120e139 mm Hg
systolic and 80e89 mm Hg diastolic. Pre-hypertension has
greater risk of developing hypertension,49 and itself carries
increased cardiovascular events risk independent of other
factors.50 The hypertensive patients exhibit higher levels of
dyslipidaemia.51e54
3. Formation of atheromatous plaques
In microvasculature, decreased blood flow increases shear
stress which results in decrease of NO production. Inhibitory
control of NO on NFkB activity is therefore lost. This results in
increased transcription of genes for inflammatory products.
Activation of NFkB in microvasculature and TGF-beta (trans-
forming growth factor beta) pathway causes induction of
several inflammatory cytokines oxLDL, C-reactive proteins.
Deficiency of NO causes vessel smooth muscle contraction,
cellular proliferation, platelet activation, increased adhesion
molecule expression etc. Critical change in shear stress at
points of vascular bifurcations and bends appears to initiate
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dx.doi.org/10.1016/j.apme.2015.04.002
the process of atherogenesis at those sites. A monocyte che-
motractant protein (MCP-1) causes accumulation of mono-
cytes in vascular intima and their transformation into
macrophages is crucial to pathogenesis of atheromas.55 There
is macrophage activation with release of mediators for
smooth muscle hyperplasia and raised extracellular matrix
especially collagen type I.56
Atherogenic plaque development involves multiple extra
and intracellular signals, engaging cells from the immune
system and from vasculature. Cross talk among atheroma
interacting cell types is seen to occur leading to increased
activation of Signal Transducer and Activator of Tran-
scriptome1 (STAT1) and elevated expression of proin-
flammatory mediators.57 IFNr and TLR4 are the key factors
contributing to every stage of plaque development. STAT1
dependant differential integration of signals between IFNr
and TLR4 in vascular cells and atheroma interacting immune
cells, results in increased leukocyte attraction, adhesion,
VSMC proliferation and migration, which are important fea-
tures of endothelial cell dysfunction and early triggers of
atherosclerosis.
4. Plaque rupture and clinical consequences
In advanced atherosclerosis, ox-LDL by its cytotoxic effect
causes apoptosis of surrounding cells leading to plaque
rupture. This may activate pro-coagulant pathways via
platelet aggregation and thrombotic consequence. Evolution
of atherosclerotic lesion towards complications involves
repeated intra plaque haemorrhages (IPH). IPH is main deter-
minant of plaque evolution toward rupture. Inward sprouting
of neo-angiogenesis from adventitia toward the plaque across
media is one source of IPH in the plaque. This is initiated by
lipid mediators generated by the plaque on luminal side and
convicted to smooth muscle cells. In response, the PPAR-
gamma receptors on the vascular smooth muscle cells are
stimulated leading to increased expression of VEGF (vascular
endothelial growth factor), responsible for neo-angiogenesis.
The neo-vessels are highly susceptible to leakage. RBCs are
the main cells in IPH bearing hemoglobin and membrane rich
in unesterified cholesterol. These participate in oxygen free
radical production as well as cholesterol accumulation. Pres-
ence of iron, glycoprotein A and ceroids in IPH also make that
focus for white cell attraction and probable infection.58 The
macrophages secrete enzymes as collagenase, gelatinase,
cathepsin etc. These degrade matrix and cause desquamation
of endothelial cells. Atherosclerotic plaques having thin
fibrous cap with high inflammation and increased proteases
including metallo-proteinases (MMPs) are vulnerable to
rupture. Initiation of breakdown of collagen cap requires
interstitial collagenases, a subfamily of MMP-1, 8 and 13.
Among these, MMP8 is most important to rupture and is
derived from leukocytes infiltrating the plaque as part of
inflammation. The fibrous collagen cap is produced by arterial
smooth muscle cells.59 Plaque rupture exposes basement
collagen, triggering platelet aggregation and thrombotic con-
sequences e.g. acute coronary syndrome.60 Matrix
metalloproteinase-14 in the plaque increase vulnerability to
rupture. Over-expression of tissue inhibitor of
 a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e7
metalloproteinase-3 (TIMP3) is protective against plaque
rupture. The more foamy macrophages are rich with MMP-14
while less foamy contain TIMP3.61
Immunological insight is also increasing. Balance of TH-17
(T helper 17) to T reg (T suppressor) lymphocytes is found
important in preventing progression of atherosclerotic plaque.
Increased TH-17 with decreased Treg function leads finally to
acute coronary syndrome.62 Loss of matrix synthesizing
smooth muscle cells would weaken and rupture the plaque.
Inflammation increases activated mast cells in plaque which
secrete mediators such as heparin proteoglycans which inhibit
SMC proliferation and collagen synthetic activity. Chymase
degrades extracellular matrix to disrupt and apoptose SMCs.
Mast cells are thus, participants in plaque rupture63
5. Remediation considerations
Efforts to delay progression of atherosclerosis and its clinical
sequele aim at controling risk factors e.g. obesity, hyperten-
sion, diabetes, dyslipidaemia and infections (chronic). Resort
to platelet function inhibitory and vasorelaxing therapies are
also relevant. Dietary and lifestyle measures to rid off obesity
are important. Surgical removal of excess visceral fat is rele-
vant but the quantitative impacts remain uncertain.28 Good
control of diabetes is most useful approach to improve
endothelial function. Statins (lipid lowering agents) and ACE
inhibitors (antihypertensive) possess welcome potentials for
correcting endothelial dysfunction.44 Anti-hypertensives with
peripheral vasodilatory effect particularly appear to improve
endothelial function.64 Newer novel beta adrenoceptor
blockers impressively correct endothelial dysfunction.65 Sta-
tins have emerged as first line agents to delay progression of
atherosclerosis but the benefits exhibit marked individual
variations.66 Situations of increased atherosclerosis risk
involve lipoperoxidation, viz smoking,67 Diabetes mellitus68
and the phenotype is characterized by small dense LDL.69
There is no apparent benefit of anti-infective therapy in
stopping progression of atherosclerosis.
Melatonin is currently of great research interest in context
of new anti atherosclerosis therapy. It regulates immune
system and circadian cycles via the nuclear receptor of the
retinoid related orphan nuclear hormone receptor family.
These may be involved in regulation of antioxidant enzyme
and anti-inflammatory genes.70,71 Nuclear receptors (NRs)
regulate gene transcription through binding to specific DNA
sequences known as RESPONSE ELEMENTs. These are located
in the promoter region of their target genes. Melatonin sup-
presses NFkB binding to DNA via a nuclear receptor cross-talk,
decreasing levels of TNF-alfa, iNOS, COX2 and PGE2 lev-
els.72e74 Production of IL2 and IL6 by mononuclear cells are
repressed.75 Melatonin enhances the nuclear transcription of
anti-inflammatory factor Nrf2 and diminishes DNA binding
capacity of pro-inflammatory factor NFkB subunit p65, and
also epigenetically affects gene expression of Nrf2 and NFkB,
per se. Melatonin not only directly neutralizes free radicals,
but prevents their production by inhibiting inflammatory
events and boosting antioxidant defenses.
Role of antioxidants in the prevention of atherosclerosis is
supported by several lines of evidence.76e78 Beneficial effects
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5
of omega3 fatty acids and their relation to antioxidant ca-
pacity is amply reported. Even omega6 acids add such effects
in certain contexts.79 Endogenous enzyme superoxide dis-
mutase and glutathione peroxidase are antioxidant defense
components and modulate synthesis of cell signaling mole-
cules that regulate oxidative stress.80 Dietary micronutrients,
manganese, zinc, copper and selenium can act as cofactors for
endogenous enzymes, whose activity may be jaeopardized
amid deficiency of these nutrients.81,82 There is lack of con-
sistency however, in reports of benefits of antioxidant sup-
plements. The descrepancies apparently emphasize
significance of attainable fine physiologic balance between
ROS production and neutralization, at tissue level.
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
systems. First kind drugs work in very specific contexts. Sec-
ond type drugs cause unwanted side and adverse effects. Gene
specific control of TLR induced inflammatory response may
help selective modulation of inflammation. Inhibitors of TLR
signaling may control inflammation, but jaeopardise other
functions subserved by the TLR induced genes. Recent evi-
dence suggests that many inflammatory genes are regulated
by epigenetic modification of individual promoters. Gene
specific control of functional subgroups of inflammatory
genes is an emerging paradigm for modulation of innate im-
mune responses, and developing novel agents for chronic
inflammatory diseases.83,84 Notwithstanding innovative sci-
entific contemplations, prophylactic antiplatelet aspirin
therapy holds ground of rationality as well as efficacy.85
Chronic inflammatory endothelial dysfunction underlies
atherothrombotic disorders. Refined strategiess of addressing
individual and synergic groups of risk factors for endothelium
biology remain at core of aspired advances.
Conflicts of interest
All authors have none to declare.
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