Clinical Science (2007) 112, 375–384 (Printed in Great Britain) doi:10.

1042/CS20060247 375

R E V I E W

Vascular inflammation in hypertension

and diabetes: molecular mechanisms
and therapeutic interventions

Carmine SAVOIA and Ernesto L. SCHIFFRIN

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University,
3755 Côte Ste-Catherine Road, Montreal, QC, Canada H3T 1E2

A B S T R A C T

More than 80 % of patients with Type 2 diabetes mellitus develop hypertension, and approx. 20 %
of patients with hypertension develop diabetes. This combination of cardiovascular risk factors
will account for a large proportion of cardiovascular morbidity and mortality. Lowering elevated
blood pressure in diabetic hypertensive individuals decreases cardiovascular events. In patients
with hypertension and diabetes, the pathophysiology of cardiovascular disease is multifactorial,
but recent evidence points toward the presence of an important component dependent on a low-
grade inflammatory process. Angiotensin II may be to a large degree responsible for triggering
vascular inflammation by inducing oxidative stress, resulting in up-regulation of pro-inflammatory
transcription factors such as NF-κB (nuclear factor κB). These, in turn, regulate the generation
of inflammatory mediators that lead to endothelial dysfunction and vascular injury. Inflammatory
markers (e.g. C-reactive protein, chemokines and adhesion molecules) are increased in patients
with hypertension and metabolic disorders, and predict the development of cardiovascular disease.
Lifestyle modification and pharmacological approaches (such as drugs that target the renin–
angiotensin system) may reduce blood pressure and inflammation in patients with hypertension
and metabolic disorders, which will reduce cardiovascular risk, development of diabetes and
cardiovascular morbidity and mortality.

INTRODUCTION in patients with hypertension [4–6]. In patients with

The frequency of diabetes mellitus is increasing rapidly
worldwide even in developing countries [1,2]. Hyperten-
sion often co-exists with diabetes, such that 60 % of
patients with diabetes are hypertensive, and up to 20 %
of subjects with hypertension are diabetic [3]. Patients
with diabetes and hypertension are at high risk, and
require effective BP (blood pressure)-lowering. Indeed,
diabetes mellitus doubles the risk of cardiovascular events
Type 2 diabetes and in hypertension, the pathophysiology
of cardiovascular disease is multifactorial, and endothelial
dysfunction, vascular inflammation and increased urine
albumin excretion develop with time and are independ-
ently associated with mortality [7].
The endothelium is the organ that bridges several
cardiovascular risk factors (e.g. hypertension, dyslipid-
aemia, smoking, diabetes and congestive heart failure) and
may be at the initiation of the development of vascular

Key words: adhesion molecule, blood pressure, cardiovascular risk factor, cytokine, diabetes, hypertension, inflammation.
Abbreviations: ACE, angiotensin-converting enzyme; Ang II, angiotensin II; ARB, angiotensin receptor blocker; AT1 , Ang II
type 1; BMI, body mass index; BP, blood pressure; COX-2, cyclo-oxygenase-2; CRP, C-reactive protein; ET, endothelin; hsCRP,
high-sensitivity CRP; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; LDL, low-density lipoprotein; MCP-1, monocyte
chemoattractant protein-1; NF-κB, nuclear factor κB; O2 •− , superoxide; PAI 1, plasminogen activator inhibitor 1; PPAR, peroxi-
some-proliferator-activated receptor; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; TNF-α, tumour
necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1; VSMC, vascular smooth muscle cell; vWF, von Willebrand factor.
Correspondence: Professor Ernesto L. Schiffrin (email ernesto.schiffrin@mcgill.ca).

C 2007 The Biochemical Society
376 C. Savoia and E. L. Schiffrin
inflammation and atherosclerosis [8–10]. Endothelial
dysfunction is characterized by impaired vasomotor res-
ponse (reduced vasodilation and increased endothelium-
dependent contraction), cell proliferation, platelet
adhesion/aggregation, vascular permeability and leuco-
cyte–endothelial interactions that participate in vascular
inflammation. Endothelial dysfunction is often associated
with microalbuminuria [11], and the latter has been consi-
dered by some to be a manifestation of impaired endo-
thelial function. Microalbuminuria is perhaps the most
important indicator of the initiation of systemic vascular
injury and associated target organ damage.
Hypercholesterolaemia, hypertension and insulin res-
istance contribute to endothelial dysfunction and inflam-
mation in the vascular wall, as well as to increased lipo-
protein oxidation, smooth muscle cell proliferation,
extracellular matrix deposition, cell adhesion and throm-
bus formation, all processes involved in the development
of atherosclerosis and ischaemic heart disease [10,12,13].
Endothelial dysfunction promotes vascular inflammation
by inducing the production of vasoconstrictor agents,
adhesion molecules and growth factors [10,13]. Thus in-
flammation is a central mechanism contributing to
the progression of cardiovascular disease, and may be
involved in the triggering of myocardial ischaemia
[13,14].
Patients with cardiovascular disease present with
increased expression and plasma concentration of inflam-
matory markers and mediators [14,15], which include
CRP (C-reactive protein) and adhesion molecules, such as
selectins (P-selectin, E-selectin and L-selectin), ICAM-1
(intercellular adhesion molecule-1) and VCAM-1 (vascu-
lar cell adhesion molecule-1). Moreover, increased plasma
levels of the primary inflammatory cytokine TNF-α
(tumour necrosis factor-α), and the secondary inflam-
matory cytokine IL (interleukin)-6, as well as ICAM-1,
VCAM-1, E-selectin, vWF (von Willebrand factor) and
CRP, have been demonstrated in patients with hyper-
tension [16]. High levels of inflammatory mediators,
particularly IL-6, ICAM-1 and CRP, may be independent
risk factors for the development of hypertension [17,18].
They may also be associated with increased risk of
diabetes [19] and cardiovascular disease. Inflammation
measured by these markers, mainly CRP, may be included
in the definition of the metabolic syndrome, a con-
stellation of abnormalities (including abdominal obesity,
high blood glucose/impaired glucose tolerance, dys-
lipidaemia and high BP) that increase the risk of overt
diabetes mellitus and cardiovascular events [20]. In the
UKPDS (United Kingdom Prospective Diabetes Study),
the incidence of complications of diabetes was strongly
associated with elevated BP [6], and tight BP control in
hypertensive patients with Type 2 diabetes decreased the
risk of macrovascular disease, stroke and deaths related
to diabetes [22]. Hence lowering BP as well as therapeutic
approaches to control vascular inflammation, particularly


C 2007 The Biochemical Society
in patients with glucose intolerance or diabetes, may
provide significant clinical benefits.
In this review, we focus on the pathophysiological
role of low-grade inflammation in the vasculature of
patients with hypertension and diabetes, as well as the
role of inflammatory markers in cardiovascular disease,
in view of potential therapeutic interventions to reduce
cardiovascular risk.
RAAS (RENIN–ANGIOTENSIN–ALDOSTERONE
SYSTEM) AND VASCULAR INFLAMMATION
Activation of RAAS plays a key role in the development
and pathophysiology of cardiovascular disease by several
mechanisms [9]. Ang II (angiotensin II) is one of the final
products and the main known mediator of the renin–
angiotensin system. Ang II induces vascular injury
through several mechanisms, including vasoconstriction,
cell growth, oxidative stress production and inflamma-
tion. Ang II modulates vascular inflammation by induc-
ing cytokine release [23] and pro-inflammatory tran-
scription factors such as NF-κB (nuclear factor κB) [24].
NF-κB, in turn, regulates adhesion molecule (VCAM-1
and ICAM-1) and cytokine expression in several cell
types [9,25]. These molecules induce and maintain inflam-
mation within the vascular wall, stimulate deposition of
extracellular matrix and promote hypertrophy and/or
hyperplasia of VSMCs (vascular smooth muscle cells)
[26]. Ang II also stimulates the production of PAI-1
(plasminogen-activator inhibitor-1) [27], which contri-
butes to the prothrombotic state as well as to athero-
sclerotic plaque rupture. Moreover, Ang II is involved in
atherosclerotic lesion progression and plaque instability
by stimulating the activation of MMPs (matrix metallo-
proteinases), which can digest the fibrous cap and thereby
participate in the triggering of plaque rupture [28].
ROS (reactive oxygen species) act as signalling mol-
ecules, modulating vascular tone and structural changes
in the circulation [29], and participate in the development
and progression of atherosclerosis [30]. ROS [mainly
O2 •− (superoxide) and H2 O2 ] activate multiple signall-
ing molecules including MAPKs [mitogen-activated
protein kinases; (p38MAPK, JNK (c-Jun N-terminal
kinase), ERK (extracellular-signal-regulated kinase)-1/2
and ERK-5], non-receptor tyrosine kinases [Src, JAK-2
(Janus kinase-2), STAT (signal transducer and activator of
transcription), p21Ras, Pyk-2 and Akt], receptor tyrosine
kinases [EGFR (epidermal growth factor receptor),
IGFR (insulin-like growth factor receptor) and PDGFR
(platelet-derived growth factor receptor)], protein tyro-
sine phosphatases and redox-sensitive transcriptor factors
[NF-κB, AP-1 and HIF-1 (hypoxia-inducible factor-1)]
(Figure 1) [26,29]. The major source of vascular ROS
is NADPH oxidase, which is expressed in endothelial
cells, VSMCs, fibroblasts and monocytes/macrophages
 Vascular inflammation in hypertension and diabetes 377

Figure 1 Molecular mechanisms of vascular inflammation

Abbreviations: AA, arachidonic acid; CAM: cell adhesion molecule (ICAM-1 and VCAM-1); EC, endothelial cells; EGFR, epidermal growth factor receptor; IGFR, insulin-like
growth factor receptor; I-κB, inhibitory κB; JAK, Janus kinases; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C;
PLA2 , phospholipase A2 ; PLC, phospholipase C; PLD, phospholipase D; STAT, signal transducers and activators of transcription; TPA, tissue plasminogen activator.

[31,32]. Ang II, ET (endothelin)-1 and inflammatory
mediators can modulate basal NADPH oxidase-induced
O2 •− production by the expression of NADPH oxidase
subunits [33]. Ang II-mediated activation of NADPH
oxidase [34] involves cSrc, PKC (protein kinase C),
PLA2 (phospholipase A2 ) and PLD (phospholipase D)
pathways, as well as increased synthesis of most of its
subunits [29,35]. In hypertension, these processes may
be enhanced [33], contributing to increased activation of
NADPH oxidase and consequent oxidative stress in the
vascular wall [9].
Increased ROS levels in hypertension impair endo-
thelium-dependent vascular relaxation by reducing NO
(nitric oxide) bioavailability [34] and increasing vascular

C 2007 The Biochemical Society
378 C. Savoia and E. L. Schiffrin
contractile responses. Ang II-stimulated NADPH oxi-
dase induces ICAM-1 expression, macrophage infiltra-
tion and vascular hypertrophy, independently of BP elev-
ation [36]. Macrophages infiltrating the adventitia or the
media of blood vessels may mediate oxidative stress gen-
erated by NADPH oxidase, also in response to elevated
BP [36]. We recently reported [37] that osteopetrotic mice
deficient in mCSF (murine colony-stimulating factor)
and accordingly monocytes/macrophages in the vascular
wall present less oxidative stress and less induction of
inflammatory molecule up-regulation in the vasculature
by Ang II, and develop less endothelial dysfunction and
vascular remodelling, suggesting a central role for macro-
phages and pro-inflammatory mediators in Ang II-
induced vascular injury.
Ang II induces aldosterone synthesis through stimul-
ation of AT1 (Ang II type 1) receptors in the adrenal
cortex. Aldosterone increases tissue ACE (angiotensin-
converting enzyme) activity [38] and up-regulates angio-
tensin receptors [39], which suggests the existence of a
vicious cycle that may potentiate the effect of the RAAS.
The activation of mineralocorticoid receptors may con-
tribute to cardiovascular dysfunction, inflammation,
fibrosis and vascular damage. Several animal models have
confirmed that aldosterone and other mineralocorticoids
can cause injury of the vasculature of the brain, heart and
kidneys by inducing ROS formation and endothelial dys-
function [40]. Mineralocorticoid antagonism attenuates
this damage by mechanisms that appear to be independent
of changes in BP, involving direct pro-inflammatory and
pro-fibrotic effects that may involve activation of the
ET system [41–44]. Mineralocorticoid receptor blockade
also improved endothelial function and reduced oxidative
stress in Ang II-infused rats [45], suggesting that aldo-
sterone induces actions usually attributed to direct effects
of Ang II. Moreover, aldosterone may induce endothelial
dysfunction and inflammation through activation of
COX-2 (cyclo-oxygenase-2) in normotensive and hyper-
tensive rats [46].
Ang II-induced inflammation via NF-κB and AP-1
activation involves, in part, ET receptors [47]. ROS
are potent stimulators of ET-1 synthesis by endothelial
cells and VSMCs [48]. ET-1 activates NADPH oxidase,
as well as other sources of ROS, including xanthine
oxidase and mitochondria, to produce increased oxidant
stress in VSMCs and blood vessels [49–52]. ET-1-induced
oxidative stress elicits inflammatory responses and con-
tributes to the vascular remodelling and endothelial dys-
function found in hypertensive models that exhibit an
ET-mediated component [53]. ETA receptor antagonism
decreases oxidative stress, normalizes hypertrophic re-
modelling, decreases collagen and fibronectin deposition,
and reduces ICAM-1 levels in the vasculature of aldo-
sterone-infused rats [44]. When human preproET-1 was
transgenically overexpressed in the endothelium, mice
exhibited endothelial dysfunction and increased activity


C 2007 The Biochemical Society
of NADPH oxidase, leading to enhanced oxidative stress
and vascular inflammation [51].
Considering the pro-inflammatory effects of Ang II
and aldosterone, agents that interfere with the compo-
nents of RAAS, such as ACE inhibitors, ARBs (angio-
tensin receptor blockers) and mineralocorticoid receptor
antagonists (spironolactone or the more selective epler-
enone), represent logical therapeutic tools to reduce
vascular inflammation and cardiovascular risk, as sug-
gested in large clinical trials in patients with hypertension
and diabetes. However, BP reduction by itself may also
influence inflammation, since calcium channel blockers
not only decreased BP in patients with hypertension,
but also reduced plasma concentrations of ICAM-1,
E-selectin and vWF [54].
INFLAMMATORY MARKERS, CLINICAL
OUTCOME AND THERAPEUTIC BENEFITS
IN CARDIOVASCULAR PATIENTS
CRP
Endothelial damage/dysfunction is associated with
markers of inflammation in patients with hypertension
and/or diabetes. hsCRP (high-sensitivity CRP) has been
related to insulin resistance, systolic BP, pulse pressure
and hypertension [55,56], and to markers of endothelial
dysfunction (plasma levels of vWF, tissue plasminogen
activator and cellular fibronectin) [57]. Elevated levels of
CRP predict development of the metabolic syndrome,
at least in women [58]. This association is even stronger
when combined with BMI (body mass index). hsCRP
and PAI-1 levels are elevated in subjects with insulin
resistance, with levels that are higher than in patients
with coronary artery disease [59]. Thus low-grade inflam-
mation in the pre-diabetic state is associated with in-
creased insulin resistance. Although subjects with insulin
resistance had greater adiposity, levels of hsCRP were not
influenced by BMI. However, hsCRP levels were higher
among the high-BMI subgroup of subjects who did not
develop diabetes during follow-up.
Numerous epidemiological studies have shown that
plasma hsCRP level is a powerful predictor of ischaemic
cardiovascular events in patients with stable or unstable
angina, appears to correlate with softer plaques that are
more prone to rupture, and may even predict cardiovas-
cular events among apparently healthy subjects [60,61]. It
may thus be useful in targeting medium-risk patients who
could benefit from aggressive cardiovascular prevent-
ative therapy. Furthermore, hsCRP levels are positively
associated with systolic BP, pulse pressure and incident
hypertension [55]. Thus CRP and high BP in combination
have additional predictive value for cardiovascular
outcomes, as they contribute as independent determin-
ants of cardiovascular risk.

CRP may be more than an inflammatory marker of
increased cardiovascular risk. CRP has been demonstra-
ted in atherosclerotic plaques and appears to be involved
in foam cell formation, promotes monocyte chemotaxis
and facilitates LDL (low-density lipoprotein) uptake by
macrophages in vitro [62,63]. In endothelial cells, CRP
facilitated the release of PAI-1 [64] and ET-1 [65], and
increased the expression of cell adhesion molecules [66],
reduced NO bioavailability [67] and NO-mediated di-
lation in the vasculature. In VSMCs, CRP induced the
expression of AT1 receptors and enhanced AT1 receptor-
mediated ROS formation, which reduced NO bioavail-
ability [68] and activated stress-activated p38 MAPK and
JNK [69]. However, CRP may also have anti-inflam-
matory actions by inhibiting neutrophil activation and
adhesion [70] and blocking platelet aggregation in vitro
[71].
A Mediterranean-style diet has beneficial effects on
endothelial function and vascular inflammatory markers
in patients with metabolic syndrome. Patients consuming
a Mediterranean-style diet had a significant reduction in
serum concentration of hsCRP, IL-6, IL-7 and IL-18, as
well as in insulin resistance [72]. Exercise training, to-
gether with weight loss, reduced hsCRP levels signific-
antly, although not in proportion to weight reduction
[73]. CRP decrease was observed in the middle weight-
reduction quartile, suggesting that there may be an opti-
mal link between exercise and weight loss with respect to
the inflammatory status [73].
In patients with high LDL-cholesterol levels, those
with low hsCRP have better clinical outcomes than
those with higher levels [74,75]. Fenofibrate lowered
hsCRP levels in patients with hypertriglyceridaemia or
combined hyperlipidaemia [76]. Statin-induced reduction
of atherosclerosis progression was significantly related
to greater reduction of hsCRP levels. Simvastatin or
atorvastatin induced the reduction of CRP in coron-
ary patients with hyperlipidaemia [77]. Interestingly,
in patients with diabetes with hypercholesterolaemia,
simvastatin combined with the ACE inhibitor ramipril
significantly reduced CRP levels more than monotherapy
alone [78].
CRP-induced up-regulation of the AT1 receptor was
attenuated by losartan [69]; on the other hand, losartan,
irbesartan nor candesartan reduced serum CRP signific-
antly in patients with hypertension [79]. A recent study,
the Val-MARC (Valsartan-Managing blood pressure
Aggressively and evaluating Reductions in hsCRP) study,
has suggested that valsartan, but neither hydrochloro-
thiazide nor both combined, reduced CRP slightly [80].
Other agents may have anti-inflammatory vascular ac-
tions, such as the PPAR (peroxisome-proliferator-activ-
ated receptor)-γ agonist rosiglitazone, which reduced
CRP levels in patients with Type 2 diabetes [81]. Rosi-
glitazone also inhibited the CRP-induced attenuation of
survival, differentiation and function of endothelial pro-
Vascular inflammation in hypertension and diabetes 379
genitor mediated, in part, by reducing the expression of
eNOS (endothelial NO synthase) [82].
Cytokines (TNF-α and ILs)
TNF-α is a primary inflammatory cytokine secreted
by several cell types involved in vascular inflammation
(endothelial cells, VSMCs and macrophages). It enhances
monocyte recruitment into atherosclerotic lesions in
early stage atherosclerosis [83]. Patients with increased
risk of recurrent coronary events have persistently elev-
ated plasma levels of TNF-α. Weight loss in obese patients
reduced plasma levels of TNF-α [84]. In patients with
hyperlipidaemia, treatment with simvastatin and the
PPAR-α agonist fenofibrate significantly reduced plasma
levels of TNF-α [85]. Moreover, in patients with hyper-
tension or obese subjects, candesartan or rosiglitazone
lowered TNF-α [86,87].
IL-1 is an inflammatory cytokine involved in the early
stages of the inflammatory process. Plasma levels of IL-1
are elevated in patients with coronary artery disease [88].
IL-6 is a secondary inflammatory cytokine which induces
the increase of plasma concentrations of fibrinogen,
PAI-1 and CRP and, in healthy men, elevated levels of
IL-6 are associated with increased risk of future myocar-
dial infarction [89]. IL-18 is an IFN-γ (interferon-γ )-
inducing factor, which is one of the strongest predictors
of cardiovascular death as well as of development of
Type 2 diabetes [90,91]. Weight loss, a Mediterranean-
style diet and exercise reduce serum concentrations of
IL-6, IL-7 and IL-18 in obese subjects [72,92]. Statins
induce a significant reduction in IL-1 and IL-6 levels
[93]. Inhibition of RAAS with either enalapril or losartan
in patients with stable angina contributed to a decrease in
the release of IL-1 and IL-6 [94]. PPAR-α ligands inhibit
production of IL-6 as well as prostaglandins and COX-2.
These effects occur as a consequence of PPAR-α-induced
inhibition of signalling by the pro-inflammatory medi-
ator NF-κB and induction of apoptosis [95]. The action of
PPAR-γ activators on inflammatory markers is a matter
of controversy. Some studies have demonstrated that
PPAR-γ activators inhibit the expression of TNF-α, IL-1
and IL-6 [96]. On the other hand, rosiglitazone did not
reduce IL-6 levels in patients with Type 2 diabetes, and
may enhance inflammatory responses in epithelial cells by
potentiating TNF-α-induced production of IL-6 and/or
IL-8 [97], although it reduces CRP levels [81,96]. Never-
theless, several studies have demonstrated that activ-
ation of PPAR-γ exerts anti-atherosclerotic actions [98].
Adhesion molecules, CD40 ligand and
MCP-1 (monocyte chemoattractant
protein-1)
Adhesion molecules, which regulate leucocyte migration
into the vascular wall, have been implicated in


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380 C. Savoia and E. L. Schiffrin
atherosclerosis, thrombosis and restenosis following
coronary angioplasty [99]. Increased expression of
ICAM-1, E-selectin and VCAM-1 have been demon-
strated in the media of blood vessels in experimental
models of hypertension, including SHR (spontaneously
hypertensive rats) and Ang II-infused rats [37,100]. Serum
concentrations of VCAM-1 and ICAM-1 are increased
in subjects with systemic vascular inflammation, Type 2
diabetes and cardiovascular disease. A stepwise increase
of age-adjusted soluble ICAM-1 and VCAM-1 levels was
shown across tertiles for carotid intima-media thickness
[101]. In the Physician’s Health Study, subjects with
ICAM-1 levels in the highest quartile presented higher
cardiovascular risk than patients in the lowest quartile
[102]. Moreover, patients with coronary artery disease
have serum concentration of adhesion molecules higher
than healthy control subjects [103].
Soluble ICAM-1 and E-selectin have been positively
correlated with central obesity. In obese subjects, a weight
reduction programme by diet and physical exercise in-
duced reductions of ICAM-1 and E-selectin, together
with body fat, after 3 months [104]. The benefit of lifestyle
modification on metabolic and inflammatory parameters
was also recorded in postmenopausal women who after a
2-week high-fibre and low-fat diet together with aerobic
exercise, had reduced serum glucose concentrations,
improved insulin sensitivity and lowered hsCRP and
ICAM-1 levels [105].
Several pharmacological approaches to improve
metabolic parameters and BP induce favourable effects on
adhesion molecules, as for other inflammatory markers
discussed above. In patients with hypercholesterolaemia,
simvastatin as well as candesartan significantly reduced
ICAM-l levels [106,107]. In subjects with hypertrigly-
ceridaemia, the PPAR-α agonist fenofibrate induced a
reduction in serum adhesion molecules [108]. In non-
diabetic patients with coronary artery disease, the PPAR-
γ activator rosiglitazone had a neutral effect on ICAM-1
and VCAM-1, as well as on flow-mediated dilation, al-
though it reduced insulin resistance, hsCRP and vWF
significantly [109].
CD40 ligand is a pro-inflammatory molecule involved
in atherothrombotic processes. It is expressed on T-lym-
phocytes (CD4+ ) and activated platelets, and interacts
with CD40 expressed on endothelial cells [110]. Plasma
levels of soluble CD40 ligand are particularly elevated
in patients with unstable angina [111], and represent an
independent predictor of cardiac death or recurrent myo-
cardial infarction in patients with acute coronary syn-
drome [112]. In patients with hypercholesterolaemia,
statins reduced plasma levels of CD40 ligand [113],
possibly by reducing NF-κB signalling [114]. Moreover,
ARBs lowered serum levels of CD40 ligand in patients
with hypertension, independently of BP reduction
[115]. In diabetic ischaemic patients, PPAR-γ activators
induced the same favourable effect [116].


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MCP-1 is a member of the C-C chemokine family and
is a potent chemotactic factor for monocytes [117]. It is
produced constitutively, or after induction by oxidative
stress, cytokines or growth factors, by a variety of cell
types, including monocytes, smooth muscle cells and
endothelial cells [118]. Increased expression of MCP-1
mRNA or protein has been observed in animals and
humans with arteriosclerosis or atherosclerosis [119].
MCP-1 levels are elevated in patients with angina,
and a further increase was observed in patients with
unstable angina [120]. Physical exercise, mainly when
combined with statin therapy, reduced MCP-1 levels
in subjects with metabolic syndrome [121]. In patients
with hypertension, ARBs reduced MCP-1 levels [122].
In the presence of hypercholesterolaemia in patients with
hypertension, combination therapy with statins and
either ARBs or ACE inhibitors was better than mono-
therapy in reducing MCP-1 levels [123,124]. Finally,
PPAR-γ activators have beneficial effects on MCP-1, as
demonstrated in experimental [125] and clinical settings
[81].
CONCLUSIONS
Low-grade inflammation occurs in the vasculature in
several conditions that predispose to cardiovascular dis-
ease, including hypertension and diabetes. Non-pharm-
acological (weight loss, exercise and Mediterranean-style
diet) and pharmacological approaches (statins, ACE
inhibitors and ARBs) reduce vascular inflammation in
patients with diabetes and hypertension, resulting in re-
duced cardiovascular events in randomized clinical
trials. Novel therapeutic approaches with PPAR-α and
PPAR-γ activators have increasingly been demonstrated
to exert cardiovascular-protective effects, independently
from their metabolic actions. Indeed PPAR activators
lowered BP, induced favourable effects on the heart and
corrected endothelial dysfunction through antioxidant,
anti-inflammatory, antiproliferative, antihypertrophic
and antifibrotic effects. Although this class of drugs could
become useful in the prevention of cardiovascular disease,
recent studies with dual PPAR activators have cast doubts
on their clinical efficacy in cardiovascular prevention
compared with the original PPAR activators currently
marketed. This being said, there is increasing evidence of
the pathophysiological role played by inflammation in the
progression of cardiovascular and metabolic disease and
in the triggering of cardiovascular events, and the need to
counter these mechanisms pharmacologically to improve
cardiovascular outcomes.
ACKNOWLEDGMENTS
The work of the authors was supported by grants 13570
and 37917 (to E. L. S.) from the Canadian Institutes of
Health Research.

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