Current Medicinal Chemistry, 2010, 17, ????-????

Inflammation, Adiponectin, Obesity and Cardiovascular Risk

H. Mangge*,1, G. Almer1, M. Truschnig-Wilders1, A. Schmidt2, R. Gasser2 and D. Fuchs3
1

Clinical Institute of Medical and Chemical Laboratory Diagnosis and Centre of Medical Research (ZMF); 2Department
of Cardiology and Centre of Medical Research (ZMF), Medical University Graz, Graz, Austria; 3Division of Biological
Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
Abstract: The development of atherosclerotic lesions leading to myocardial infarction (MI) or stroke encompasses a cascade of cellular and molecular events that can well be characterized as a chronic immune-mediated inflammation occurring preferentially in the biologic surrounding of the so called metabolic syndrome. Adipokines, chemokines, cytokines,
and their receptors are critically involved in the initiation and perpetuation of atherosclerosis, and they play important
roles at all levels in the pathogenesis of this disease. Metabolic risk profiles associated with sedentary lifestyle, obesity,
especially intra-abdominal fat accumulation, insulin resistance, and dyslipidemia pave the way for a chronic, immunemediated vascular inflammation around vascular lipid deposits. In the present article, the impact of adiponectin, monocyte
and T-cell associated cytokines (with emphasis on Neopterin), individual adipose tissue - distribution, and pleiotropic
drug effects on the individual course of atherosclerosis and associated cardiovascular disease are reviewed.

Keywords: ???????????????????????????. adiposity, immune-mediated inflammation, cardiovascular risk,

INTRODUCTION
The "diabesity pandemic" causes an explosion in rates of
obesity, and type 2 diabetes in the industrialized countries
[1]. Thus, cardiovascular disease (CVD), a major sequel of
diabesity, is the leading cause of death and illness, and will
become the prevalent health problem worldwide [2]. Cardiovascular disease is caused by atherosclerosis (AS), a chronic,
progressive process characterized by the accumulation of
lipids and fibrous elements in the arteries. The link between
lipid metabolism and atherosclerosis dominated the thinking
until the 1980s [3]. Over the last twenty years, however, a
prominent pace-maker role for immune-mediated inflammation in the pathogenesis and course of atherosclerosis has
been established [4]. Now, atherosclerosis is considered as a
systemic disease, characterized by arterial inflammatory
lesions that mature and modify themselves with disease progression [5]. The underlying pathophysiologic process is
driven by complex interactions between "systemic" metabolic risk factors most frequently associated with obesity,
leucocytes, platelets and cells of the vessel wall. The earliest
vascular lesions - the fatty streaks - primarily consist of
inflammatory cells such as monocyte derived macrophages
and T-lymphocytes [6], and can be detected already in obese
children [7]. However, obesity is no strict one-way to symptomatic AS associated with overt CVD later in life. In the
following, we review the impact of monocyte and T-cell
associated cytokines with special emphasis on neopterin,
obesity and adiponectin the most important antiinflammatory
adipokine, on the individual course of atherosclerosis towards endpoints such as myocardial infarction (MI).
INITIATION OF ATHEROSCLEROSIS
Endothelial injury is considered as the first and crucial
step in the pathogenesis of atherosclerosis [3]. A plethora of
genetically determined and epigenetic factors, such as
*Address correspondence to this author at the Clinical Institute of Medical
and Chemical Laboratory Diagnosis, Medical University of Graz, Auenbruggerplatz 30, 8036 Graz, Austria; Tel: +43 316 385 8 33 40; Fax: +43
316 385 4024; E-mail: harald.mangge@klinikum-graz.at
0929-8673/10 $55.00+.00

oxidized LDL, free radicals (e.g. due to cigarette smoking),

hypertension, diabetes mellitus, obesity, elevated plasma
homocysteine, infectious microorganisms, autoimmune reactions, and combinations thereof, have been discussed as etiological principles (Fig. 1).
It is now well established that the infiltration of lowdensity lipoproteins (LDL) in the vascular wall is the pivotal
step in plaque formation [8]. Oxidative and enzymatic modifications of retained LDL increase the expression of adhesion molecules on endothelial cell surface membrane, thus
favoring leukocyte recruitment from the blood stream [9].
Endothelial injury perpetuates inflammation with increased
adhesiveness and activation of monocytes, which is accompanied by the production of cytokines, chemokines, metalloproteinases, vasoactive molecules, and growth factors. The
recruitment of leukocytes within atherosclerotic plaques is
essentially orchestrated by the binding of chemokines to
their cellular receptors. Such chemokine receptors are fractalkin receptor (CXC3CR1), and monocyte chemoattractant
protein receptor (CCR2) [9]. This redundant system regulates all inflammatory phases of atherogenesis. The resident
monocyte subset phenotype (CXC3CR1hiCCR2
Ly6Clow
CD14lowCD16+) is mainly involved in the initiation of vascular inflammation, angiogenesis and atheroprogression [10].
Symptomatic atherosclerosis (AS) is usually associated
with advanced age. However, observations by autopsy and
carotid sonography revealed the presence of atherosclerotic
lesions also in adolescence and even in childhood [11, 12].
This is confirmed by our own observations. We analyzed the
low grade inflammatory activity in a cohort of juveniles (520 years) with obesity, as compared to healthy, normal
weight, age matched controls. The obese juveniles showed
low grade inflammation as detected by significantly increased high sensitive C-reactive protein (hsCRP). Ultrasonography revealed that obese juveniles, as compared to
controls, exhibited a significantly increased intima-media
thickness (IMT) of common carotid arteries (CCAs) [13].
These observations identify AS as an extremly, chronic,
longlasting disease starting very early in life.

2010 Bentham Science Publishers Ltd.

Current Medicinal Chemistry, 2010 Vol. 17, No. 31

Mangge et al.

Fig. (1). The complex pathogenesis of atherosclerosis: Involvement of lipid metabolism, adipokines, genetic predisposition, infection and
autoimmunity.

PERPETUATION OF ATHEROSCLEROSIS
If the acute inflammatory response does not eliminate the
causative agent(s), a chronic inflammation ensues. Thickening is compensated by dilation, and up to a certain point, the
lumen remains unaltered (i.e.remodelling) [14]. As in all
stages of atherosclerosis, this phase is also dominated by
monocyte-derived macrophages and T lymphocytes [4, 15,
16], granulocytes are rare (Fig. 2). The ongoing process is
characterised by cyclic accumulation of mononuclear cells,
exaggerated growth of the lipid core, and formation of fibrous tissue leading to enlargement and restructuring of the
lesion.
EFFECTOR CELLS OF ATHEROSCLEROSIS
Monocytes/Macrophages
Play an ambiguous role. In the early phase, they are considered rather protective [17]. Later on, they stimulate the
vicious cycle of cytokine/chemokine/metalloproteinase production and cell recruitment, which leads to perpetuation of
the arterial inflammation [17]. Monocytes were considered
as the crucial force to drive atherogenesis [10]. Monocyte
products, such as tumor necrosis factor alpha (TNF-
), interleukin-(IL)-1, metalloproteinases, and growth factors [e.g.
insulin-like growth factor 1 (IGF-1)] are critical in the damage and repair, that ensue as the lesions progress [18] (Fig.
2). Two monocyte subsets were identified [i.e. (CXC3CR1hi
CCR2
Ly6ClowCD14lowCD16+) and (CXC3CR1lowCCR2 +
Ly6ChiCD14+CD16
)] [10]. The inflammatory subset
(CXC3CR1lowCCR2 +Ly6ChiCD14+CD16
) represents the
main population recruited to the AS lesion from the blood
stream and displays both phagocytic and proteolytic activities [10]. Modified LDL is uptaken by scavenger receptors of
resident macrophages that differentiate into different inflammatory cell types, such as dendritic-, foam-, osteoclastand osteoblast-like cells. This is modulated by several cytokines and growth factors (such as receptor activator of nuclear factor-(NF)-kappaB ligand (RANKL), osteoprotegerin
(OPG), TNF-
, granulocyte macrophage-colony stimulating
factor (GM-CSF), IL-4, and macrophage-colony-stimulating
factor (M-CSF). M-CSF furthers the transition of monocytes
to lipid-laden macrophages. Further, connexins which mediate gap junction formation between adjacent cells (vascular
and immune cells) were shown to play a central role in cell
differentiation and growth. Three different connexins (Cx37,

Cx40 and Cx43) are differently expressed in macrophage

and endothelial cells during atherosclerotic plaque maturation [19]. Chemokines, such as fractalkin (CX3CL1) and
RANTES (regulated on activation, normal T-cell expressed
and secreted) perpetuate the inflammation (Fig. 2). Creactive protein (CRP) induces M-CSF release and macrophage proliferation [20, 21]. GM-CSF aids the survival of
mononuclear phagocytes containing myeloperoxidase, which
gives rise to hypochlorous acid, a source of oxidative stress
in plaques [22]. Fractalkin (CX3CL1) and its ligand
CX3CR1, as well as platelet derived RANTES, promote
shear-resistant monocyte recruitment and lesion development
[23, 24]. Recently, also peroxisome proliferator-activated
receptors (PPARs) a family of nuclear receptors were found
to be involved in the regulation of innate inflammatory processes mostly through alteration of monocyte/macrophage
phenotypes [25].
A prominent role of macrophages in early atherogenesis
is underlined by recent findings that the macrophage-product
neopterin is a significant predictor of outcome in individuals
with angiographic coronary artery disease (CAD) [26, 27]. In
several multimarker studies, neopterin was found to add significant information, which is not adequately reflected by the
other parameters including CRP [28].
Lymphocytes
During perpetuation of atherosclerosis, resident inflammatory and vascular cells further produce chemokines for the
recruitment of T lymphocytes within the plaque. This induces the deleterious vicious circle of the immune-mediated
inflammatory response. Besides mast cells and neutrophils,
T-helper lymphocytes of type 1 (Th-1) promote the atherosclerotic inflammation (Fig. 2). Conversely, Th-2 and regulatory T-lymphocytes (Treg) rather reduce atherogenesis [10].
An altered balance between Th-1 cytokines interferon-
(IFN-), IL-12, IL-15, IL-18 and TNF-
, anti-inflammatory
cytokines (TGF-beta and IL-10) and chemokines (mainly
CCL2, CCL3, CCL5) increase immune cell functions and
recruitment in atherosclerotic plaques. Antigen-activated T
cells secrete cytokines, such as IFN-, TNF-
and  that
amplify the inflammatory response [29]. Interleukin-17 (IL17) was found to be produced concomitantly with IFN- by
coronary artery-infiltrating T cells [30]. These cytokines act
synergistically to induce pro-inflammatory responses in vascular smooth muscle cells [30]. IL-18 concentrations were
found to be increased in the peripheral blood of patients with

Adiposity and Cardiovascular Inflammation

Current Medicinal Chemistry, 2010 Vol. 17, No. 31

Fig. (2). The inhibitory role of adiponectin in initiation, perpetuation and regression of atherosclerosis.

acute CVD, and correlated with the severity of myocardial

dysfunction [31]. Further, IL-18 was linked to vulnerability
and progression of atherosclerotic plaques [32]. IL-18 correlated positively with IL-12, and negatively with IL-10, again
suggesting a T-helper 1 (Th1) dominant state in critical atherosclerosis associated with CVD [33] (Fig. 2). Probably induced by IFN-
, smooth muscle cells also express HLA-DR,
and present antigens (e.g. oxLDL) to T cells [29, 34, 35]
(Fig. 2). IL-10, a potent anti-inflammatory cytokine, was
shown to limit the progression of atherosclerosis by attenuating CD40-mediated IL-12 synthesis in human endothelial
cells [36]. Overexpression of IL-10 by T-cells inhibited advanced atherosclerotic lesions in LDL receptor lacking mice
fed with an atherogenic diet [37]. Taken together, the innate
and adaptive arms of the immune response are involved in
the initiation, progression, and ultimate thrombotic complications of atherosclerosis [38].
REDOX-REGULATION OF TH1- AND TH2-TYPE
IMMUNE RESPONSE
Within Th1-type immunity, the pro-inflammatory cytokine IFN-
is probably the most important mediator of antimicrobial and anti-tumoral defence. IFN-
induces several
immunobiological pathways including high-output of toxic
reactive oxygen species (ROS) by macrophages [39] which
interfere with various redox-sensitive intracellular signaltransduction cascades involving, e.g., translocation of nuclear factor-B (NF-B) [40] and in turn accelerate the production of pro-inflammatory cytokines like TNF-
[41]. This

background implies that antioxidants could slow-down inflammatory processes involved in atherogenesis. This interaction is plausible when intake of antioxidant-rich (Mediterranean) diet is related to a lower frequency of atherosclerosis
[42]. However, larger studies thus far were widely unable to
demonstrate a similar beneficial effect of extra-antioxidants
in patients suffering from CVD [43, 44].
From energy balance considerations it is quite obvious
that in weight-gaining individuals the essential balance between energy intake - as calories consumed by food versus
calories burned during physical activity - is disturbed. Aside
from disturbing the Th1-/Th2-type immune balance, antioxidant compounds may also play a role in the obesity epidemic, e.g., in patients with type 2 diabetes it was observed
that antioxidant supplements may prevent the healthpromoting effects of exercise [45]. Antioxidants may neutralize ROS and thus counteract exercise-induced physiological responses to ROS. This observation could be more
generally relevant. The increased mitochondrial formation of
ROS by exercise is central for burning calories [46], which
chemically represents an oxidation reaction producing CO 2
and H2O as end products. One has to expect that addition of
antioxidants is able to counteract this process. Certainly,
physical activity has declined in the average population in
the West, but in parallel the use of food supplements like
food preservatives and colorants by the food industry has
also drastically increased. Many of these additives are
strongly antioxidant chemicals, e.g., sodium sulfite and
ascorbic acid [47], just to name a few, are probably the most
widely used food preservatives. With this in mind, weight

Current Medicinal Chemistry, 2010 Vol. 17, No. 31

gain and the obesity epidemic would be no longer solely due

to eating more with less physical activity, rather the latter is
also less effective in burning calories when antioxidant food
supplements are taken in. However, any specific influence of
antioxidant supplements on adiponectin production is still
unclear [48], and epidemiological studies on this relationship
are still missing. Likewise, any conclusion on the role of
antioxidant supplements as a risk factor for weight gain and
the obesity epidemics is still far from being final.
Micro-RNAs
Recently microRNAs were shown to be centrally involved in cell proliferation, apoptosis, and differentiation
that accompany inflammatory responses. Recently, five microRNAs (microRNA-125a-5p, microRNA-9, microRNA146a, microRNA-146b-5p, and microRNA-155) were found
to be aberrantly expressed after oxLDL treatment of human
monocytes. MicroRNA-125a-5p mediates lipid uptake and
decreases the secretion of inflammatory cytokines such as
IL-2, IL-6, TNF-
, transforming growth factor-beta in
oxLDL-stimulated monocyte-derived macrophages. Thus,
MicroRNA-125a-5p appears to modulate the posttranscriptional regulation of the pro-inflammatory response
and
lipid
uptake
in
oxLDL-stimulated
monocyte/macrophages [49]. MicroRNAs may represent interesting diagnostic and therapeutic targets in the future.
LIPOPROTEINS
Oxidized-LDL essentially stimulates the inflammatory
machinery. Besides its ability to injure cells (e.g, endothelium) [50], it is chemotactic for monocytes and upregulates
the expression of genes for M-CSF [51] and monocyte chemotactic protein (MCP) [52] derived from endothelial cells.
Autoantibodies against oxLDL and autoreactive Tlymphocytes have been brought into connection with CVD
[34, 53, 54]. On the other hand, however, humoral immune
responses against oxLDL have been considered to protect
against atherosclerosis [55]. Cytokines such as TNF-
, IL-1,
IL-6, and M-CSF increase the binding of LDL to the endothelium and to smooth muscle, as well as the transcription of
the LDL-receptor gene [56-58]. Oxidized LDL initiates serial intracellular events [57] including the induction of
urokinase [59] and production of IL-1 [60, 61]. Thus, oxLDL
induces inflammatory cytokine/chemokine cascades in the
arterial wall. However, different response pathways may
influence the course of arterial inflammation triggered by
oxLDL (i.e.: perpetuation to symptomatic atherosclerosis,
steady state, remodelling, healing by removal of noxious
agents like oxLDL).
ADHESION MOLECULES
Adhesion molecules on leukocytes (integrins CD11a,
CD11b, CD11c, CD18, selectins) and endothelial cells [intercellular adhesion molecules (ICAMs), vascular adhesion
molecules (VCAMs), Platelet endothelial cell adhesion
molecules (PECAMs), junctional adhesion molecules
(JAMs)] mediate cell rolling and adhesion to the vessel wall
[62]. Local inflammation triggers systemic organs to release soluble inflammatory mediators, such as C-reactive

Mangge et al.

protein (CRP), endocannabinoids, cytokines (IL-6, TNF-
,

IFN-, adipokines) and hormones that further perpetuate the
inflammatory activation [63, 64]. Smooth muscle cells migrate into the intima and the arterial remodelling becomes
irreversible which may cause arterial lumen stenosis with
collagen and calcium deposition [64] . Once recruited into
the intima, vascular and immune cells release toxic mediators, such as proteases and oxidants that induce atherosclerotic plaque instability. The sudden thrombotic occlusion of
the artery at site of plaque disruption induces potentially life
threatening overt clinical disease caused by ischemia in the
heart, brain and peripheral tissues.
THE ROLE OF ADIPONECTIN
It is well established now that besides energy storage the
adipose tissue constitutes a highly active endocrine organ
[65]. Adipocytes synthesize pro-inflammatory respectively
pro-atherogenic molecules like IL-6 and mononocyte
chemoattractant protein-1 (MCP-1), and also potentially antiatherogenic proteins [66] such as adiponectin [67, 68]. The
basic structure of full length adiponectin (fAd) is a 247
amino acid protein with four domains, an amino-terminal
signal sequence, a non-conserved variable region, a collagenous domain and a carboxyterminal globular domain [69]. It
circulates in different molecular weight (MW) forms, named
high-MW (oligomer), medium-MW (hexamer) and low-MW
(trimer) [70, 71] at 2 30
g/ml levels in the bloodstream
[72]. The subfractions exert markedly different biologic
functions [73]. Waki et al. showed that leukocyte elastase
secreted from activated monocytes and/or neutrophils can
cleave fAd [74]. This may be the reason for the generation of
the 16 kDa globular fragment of adponectin (gAd), which is
found in lower levels (about 1% of total adiponectin) in the
circulation [75]. Globular adiponectin increases insulinmediated glucose uptake, and boosts the -oxidation of fatty
acids [76, 77], while other functions remain controversial
[78]. Adiponectin exerts its biological effects mainly through
its receptors, AdipoR1 and AdipoR2 [79]. It also binds to Tcadherin [80] and to the multifunctional protein calreticulin
[81]. Okamoto et al. suggested that adiponectin further binds
to collagen types I, III and V, which are present in vascular
intima and that it accumulates in vascular walls when the
endothelial barrier is injured [82]. Adiponectin's gene has
been mapped at chromosome 3q27, but the mechanisms
regulating its expression are still open [83]. Adiponectin is
dysregulated in obesity [84] and type 2 diabetes mellitus
[85]. It exerts anti-inflammatory properties directly affecting
the vasculature [86]. An anti-atherogenic role of adiponectin
was supposed by the ability to modulate the expression of
endothelial adhesion molecules [87] and to influence key
mechanisms of atherogenesis via an adventitia-AMPKiNOS pathway [88]. Thus, many experimental and clinical
studies examined adiponectin in vascular homeostasis and its
potential value as a biomarker of clinical interest for cardiovascular disease, providing however contradictory results.
The expression of adiponectin is regulated by distinct
signaling pathways, involving different transcriptional factors. Studies on 3T3-L1 adipocytes have shown that oxidative stress [89], sympathetic nervous system activity [90] and
pro-inflammatory cytokines, such as TNF- and IL-6 [91],

Adiposity and Cardiovascular Inflammation

suppress adiponectin expression. Adiponectin levels were

associated with age, gender (lower in men, possibly due to
androgen effect) [92] and smoking status, while mediterranean diet and exercise increase its serum levels [93-97]. Hypoadiponectinemia is associated with obesity, metabolic
syndrome, type 2 diabetes mellitus [98], dyslipidemia [99]
and essential hypertension [100]. Hypoxia found in adipose
tissue of obese mice led to dysregulated production of adipocytokines with decreased expression and instability of adiponectin mRNA. This was associated with increased levels
of mRNA of C/EBP homologous protein (CHOP), an
endoplasmic reticulum (ER) stressmediated protein [101].
Further, genetic determinants affect adiponectin levels [93].
From 10 frequent single-nucleotide polymorphisms of the
adiponectin gene, two common single-nucleotide polymorphisms (+45T>G and +476G>T) were proposed to determine
circulating adiponectin levels [93]. However, these studies
could so far not satisfactorily address the role of gene
environment interactions [93].
Despite being a hormone secreted mainly by adipose tissue, adiponectin levels are paradoxically inversely correlated
with body weight, or body mass index [102], suggesting a
negative feedback loop between adiponectin and adipose
tissue. Adiponectin is decreased in obesity, and adiponectin
levels are increased after substantial weight loss [102]. Regarding the effect of insulin on adiponectin expression, the
data are controversial. Insulin was observed to decrease adiponectin expression [103], but at a clinical level, long-term
insulin administration to diabetic patients had no impact on
adiponectin levels [104]. Patients with particularly high insulin levels due to type B insulin resistance show also extremely high adiponectin levels [105]. Further, insulin induces a twofold rise in adiponectin gene expression in adipocytes. So far the controversial results of the clinical and experimental studies fail to provide a definite conclusion regarding the effect of insulin on adiponectin expression in
humans [106].
Adiponectin and Cardiovascular Risk
Adiponectin affects important inflammatory mechanisms
involved in CVD. It was shown recently that the production
of proinflammatory cytokines (e.g. IL-6, IL-8, MCP-1, PAI1, MIG) was increased by epicardial adipose tissue (EAT)
cells in obesity and CVD. Recombinant adiponectin reversed
these effects [107]. Ouchi et al. [87] showed that adiponectin interferes with nuclear factor kappa-B (NF-B)
intracellular signaling pathways, suppressing the expression
of adhesion molecules. TNF-
, centrally involved in vascular
tissue inflammation and controlled by NF-B, has a reciprocal relationship with adiponectin. Adiponectin knockout
mice show high TNF-
plasma levels, and TNF-
mRNA
expression in adipose tissue [108]. Adiponectin negatively
regulates IL-2-induced natural killer cell activation and inhibits the synthesis of endothelium-derived inflammatory
cytokines [109]. It induces the production of the antiinflammatory mediators IL-10 and IL-1RA in human inflammatory cells and impairs IFN-
production, another target gene of NF-B [109].
On the other hand, globular adiponectin was found to activate NF-B transcriptional pathways in vascular endothe-

Current Medicinal Chemistry, 2010 Vol. 17, No. 31

lial cells, which may promote inflammation [110]. In the

KORA S4 study, it was recently suggested that hypoadiponectinemia and pro-inflammatory state are largely independent from each other [111]. Therefore, the true impact of
adiponectin on inflammatory mechanisms is still controversial. It is likely that the underlying disease state is a key determinant of the association between adiponectin and inflammation, but adiponectin production obviously is more
related to a Th2-type cytokine pattern.
Adiponectin and Endothelial Cells
In vitro adiponectin promotes the production of nitric oxide (NO) by endothelial cells, via PI3-dependent pathways,
which enhance endothelial NO synthase (eNOS) activity by
triggering its AMPK-induced phosphorylation [112]. Cell
culture studies showed an ability of adiponectin to decrease
TNF-
-induced production of asymmetric dimethylarginine
(ADMA) [113], an L-arginine analogue that inhibits NO
formation. The activation and up-regulation of eNOS may
explain some of the observed vaso-protective properties of
adiponectin. Apart from its beneficial effects on eNOS, adiponectin improves endothelium redox state by suppressing
NADPH oxidase-derived superoxide generation [114]. Further, HMW adiponectin seems to suppress endothelial cell
apoptosis [115], and to promote vascular healing and angiogenesis [116]. Although in our investigations, i.e. STYJOBS
(Styrian juvenile obesity study), the bioavailibility of NO
was found to be decreased in obese juveniles with hypoadiponectemia and preatherosclerosis as defined by increased
intima media thickness (IMT) of common carotid arteries
(CCAs) [117], we found no correlation between serum
ADMA levels, adiponectin, and IMT [118]. Thus, early
phases of AS as found in obese juveniles appear to differ
markedly from advanced stages of AS associated with yet
present cardiovascular symptoms.
Adiponectin
(VSMCs)

and

Vascular

Smooth

Muscle

Cells

Adiponectin reduced proliferation of VSMCs in a receptor-independent way by binding to, and inhibiting, the activity of growth factors, such as heparin-binding epidermal
growth factor, basic fibroblast growth factor, and plateletderived growth factor-BB [119-121]. In adiponectin knockout mice, a high-fat and high-sucrose diet led to an increase
in intimal smooth muscle cell proliferation after injury in the
aorta [122, 123].
Adiponectin and Monocytes/Macrophages
Cholesterol efflux from macrophages is increased by adiponectin, and it inhibits in vitro the transformation of macrophages to foam cells by blocking the expression of the class
A scavenger receptor (MSR) at both mRNA and protein levels [90,91]. Controversy remains regarding the role of adiponectin for macrophage cytokine production. Wolf et al.
reported that adiponectin increases the anti-inflammatory
cytokines IL-10 and IL-1RA [124] while Tsatsanis et al.
postulated that adiponectin promotes tolerance of macrophages to pro-inflammatory stimuli [125].

Current Medicinal Chemistry, 2010 Vol. 17, No. 31

Adiponectin and Atherosclerotic Inflammation Concluding Remarks

Evidence for a protective role of adiponectin in atherosclerosis was firstly provided by animal experiments. Adiponectin knockout mice clearly showed increased neointimal proliferation in response to vascular injury [126], and
adiponectin prevented atherosclerosis in apolipoprotein-Edeficient mice [127]. However, recently crossing experiments of adiponectin knockout mice (Adn/) and adiponectin overexpressing mice (AdnTg) with low-density
lipoprotein receptornull (Ldlr/) and apolipoprotein Enull
(Apoe/) mice showed that adiponectin levels did not correlate with a suppression of the atherogenic process. Aortic
plaque volumes, cholesterol accumulations, and plaque morphology were not affected by circulating adiponectin levels
[128]. Thus the actions of adiponectin are complex and multifaceted, with a contradictory impact on atherosclerotic
plaque formation in animal models.
In accordance with these observations, the exact role of
adiponectin in human atherosclerosis and its association with
mortality remains unclear. It is generally believed that adiponectin prevents the progression of atherosclerosis. However, on the other hand, circulating adiponectin was negatively associated with common carotid intima media thickness, but not with the presence of atherosclerotic plaques
[129].
We extensively studied early phases of atherosclerosis.
As shown by the Styrian Juvenile Obesity Study
(STYJOBS), obese juveniles aged around 13 years already
had an increased carotid intima-media thickness (IMT) paralleled by a subclinical inflammation indicating preatherosclerosis [13]. Adiponectin was decreased in the obese group.
Interestingly, after multiple testing the strongest positive
correlation was seen between parameters of trunk accentuated obesity such as nuchal SAT thickness, increased IMT
and serum adiponectin [130]. Other anthropometric parameters such as waist to hip circumference or percentual body fat
showed less significant correlations. Further, we found altered subfractions of adiponectin in obese juveniles and adolescents, whereas after multiple testings the HMW subfraction was better negatively correlated to the IMT as total adiponectin [71]. We provided the first evidence that nuchal
SAT thickness is tightly positively associated with an increased LMW / total adiponectin and a decreased HMW /
total adiponectin ratio, identifying such persons as early as in
adolescence to be on very high risk for obesity related atherosclerotic vascular disease [70]. Our data clearly indicate
that independent of gender and conventional anthropometric
measurements (i.e. BMI, waist to hip ratio, percentual body
fat), trunk accentuated obesity as identified by nuchal SAT
thickness is associated with an increased risk of early vascular burden detected by IMT. This may be caused by a disturbed oligimerization from low to high molecular weight
adiponectin occurring preferentially in cases of trunk
weighted obesity [70]. In accordance, a very recent publication of the Framingham Heart Study underlines the importance of the neck circumference as the most important CVD
risk factor even after adjustment for visceral adipose tissue
and BMI [131]. These findings underline the importance of
upper-body subcutaenous fat as a unique, pathogenic fat de-

Mangge et al.

pot.
Thus, hypoadiponectinemia may have a useful clinical
value at early stages of atherogenesis, but its role as a meaningful biomarker is doubtful at more advanced disease stages
associated with CVD progression towards clinical end
points. This is also supported by the observation that adiponectin cannot be effectively used for cardiovascular risk
stratification among healthy individuals, after 20 years of
follow-up [132, 133]. The contradictory results regarding the
use of circulating adiponectin as a biomarker in atherosclerosis may be explained by the different disease stage of the
various populations included into the clinical studies so far.
As stated above, decreased circulating adiponectin in healthy
populations seems to be predictive for the development of
atherosclerosis. However, after the establishment of AS, this
association becomes weaker, especially in the presence of
conditions inducing a hyper-catabolic state such as heart
failure, which are associated with increased circulating adiponectin, accelerated progression of AS and worse clinical
outcome. Finally, it must be noted that not only in hypercatabolic states but also in chronic inflammatory / autoimmune diseases that are unrelated to increased adipose tissue,
like rheumatoid arthritis (RA), systemic lupus erythematodes
(SLE), inflammatory bowel disease, type 1 diabetes, and
cystic fibrosis adiponectin levels were found to be increased
[134]. Paradoxically, in these diseases, adiponectin levels,
positively, rather than negatively correlated with inflammatory markers [134]. Thus, more research on the role and
regulation of adiponectin in obesity-, atherosclerosis- and
autoimmunity-related chronic inflammation is clearly necessary to enlighten the complex biologic functions of this protein.
CONCLUSION
In the foregoing we have summarized the evidences that
atherosclerosis constitutes primarily an immune-mediated
chronic inflammatory disease of the arterial vessel wall with
complex implications to the pathophysiologic scenario of the
so called metabolic syndrome. Attempts should increasingly
be under-taken to make use of this knowledge in the advanced clinical routine, particularly towards early diagnosis
and the identification of individuals at risk. As pointed out
before, this may be accomplished by selecting certain serological parameters that have been largely neglected so far,
such as inflammatory markers like hsCRP and neopterin.
Investigations are still needed to clarify the potential immune-modulating, anti-inflammatory role of adiponectin as a
possible diagnostic or therapeutic target.
The second point we want to make is that the relevant
studies so far largely dealt with single adipokines, cytokines,
chemokines and their receptors measured in limited numbers
of patients. Future, improved diagnostics of atherosclerosis
should take into account the above described complexity of
this disease by means of modern techniques of proteomics,
which allow for the simultaneous analysis of a multitude of
relevant molecules and can be expected to reveal as yet unknown associations or finger print constellations. Further,
microRNAs may represent interesting new diagnostic and
therapeutic targets in the future because they are centrally
involved in the pathologic cascades, and potentially drugga-

Adiposity and Cardiovascular Inflammation

ble by so called blocking RNAs. The recognition of individual inflammatory/metabolic risk patterns, by approaches of
personalized medicine taking into accout genetic, epigenetic,
sex, age and lifestyle factors rather than the measurement of
single parameters, may give important and new information
towards early diagnosis and monitoring of atherosclerosis,
and may finally provide the basis of new therapeutic strategies.
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