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Clinical Science (2007) 112, 375384 (Printed in Great Britain) doi:10.1042/CS20060247 375

R E V I E W

Vascular inflammation in hypertensionand diabetes: molecular mechanisms

and therapeutic interventions

Carmine SAVOIA and Ernesto L. SCHIFFRINLady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University,3755 Cote 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 factorswill 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-B (nuclear factor B). 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

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, andrequire effective BP (blood pressure)-lowering. Indeed,

diabetes mellitus doubles the riskof cardiovascular events

in patients with hypertension [46]. In patients with

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-sensitivityCRP; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; LDL,low-density lipoprotein; MCP-1,monocyte

chemoattractant protein-1; NF-B, nuclear factor B; O2, superoxide; PAI 1, plasminogen activator inhibitor 1; PPAR, peroxi-

some-proliferator-activated receptor; RAAS, reninangiotensinaldosterone system; ROS, reactive oxygen species; TNF-, tumour

necrosis factor-; VCAM-1, vascular cell adhesion molecule-1; VSMC, vascular smooth muscle cell; vWF, von Willebrand factor.

Correspondence: Professor Ernesto L. Schiffrin (email [email protected]).

C 2007 The Biochemical Society

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376 C. Savoia and E. L. Schiffrin

inflammation and atherosclerosis [810]. 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-

cyteendothelial interactions that participate in vascular

inflammation. Endothelialdysfunction is oftenassociatedwith microalbuminuria [11], andthe latterhas 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 dysfunctionpromotes 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,suchas

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-

(tumour necrosis factor-), 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, mainlyCRP, maybe includedin 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

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 reducecardiovascular risk.

RAAS (RENINANGIOTENSINALDOSTERONE

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-B (nuclear factor B) [24].

NF-B, in turn, regulates adhesion molecule (VCAM-1

and ICAM-1) and cytokine expression in several cell

types[9,25]. Thesemoleculesinduce 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 digestthe fibrouscap 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 H2O2] activate multiple signall-

ing molecules including MAPKs [mitogen-activated

protein kinases; (p38MAPK, JNK (c-Jun N-terminalkinase), 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-

sinephosphatases and redox-sensitivetranscriptor factors

[NF-B, 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


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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-B, inhibitory B; 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


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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 micedeficient 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 damageby mechanisms that appearto be independent

of changes in BP, involving direct pro-inflammatory and

pro-fibrotic effects that may involve activation of the

ET system [4144]. 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-B 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 xanthineoxidase and mitochondria, to produce increased oxidant

stress in VSMCs and bloodvessels [4952]. 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

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

CRPEndothelial 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

withcoronary 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 ischaemiccardiovascular 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 usefulin 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].ThusCRP andhigh BPin combination

have additional predictive value for cardiovascular

outcomes, as they contribute as independent determin-

ants of cardiovascular risk.


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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], andincreased 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 markersin 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-inducedreduction

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)- 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-

genitor mediated, in part, by reducing the expression of

eNOS (endothelial NO synthase) [82].

Cytokines (TNF- and ILs)TNF- 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 plasmalevels of TNF-. Weight loss in obese patients

reduced plasma levels of TNF- [84]. In patients with

hyperlipidaemia, treatment with simvastatin and the

PPAR- agonist fenofibrate significantly reduced plasma

levels of TNF- [85]. Moreover, in patients with hyper-

tension or obese subjects, candesartan or rosiglitazone

lowered TNF- [86,87].

IL-1 is an inflammatory cytokine involved in the earlystages of the inflammatory process. Plasma levels of IL-1

are elevated in patients with coronary artery disease [88].

IL-6 is a secondaryinflammatorycytokine 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- (interferon-)-

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- ligands inhibit

production of IL-6 as well as prostaglandins and COX-2.

These effects occur as a consequence of PPAR--induced

inhibition of signalling by the pro-inflammatory medi-

ator NF-B andinduction of apoptosis[95].The actionof

PPAR- activators on inflammatory markers is a matter

of controversy. Some studies have demonstrated that

PPAR- activators inhibit theexpression of TNF-, IL-1

and IL-6 [96]. On the other hand, rosiglitazone did not

reduce IL-6 levels in patients with Type 2 diabetes, andmay enhance inflammatory responses in epithelialcellsby

potentiating TNF--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- 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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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 increasedin 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 Physicians 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

correlatedwith central obesity. In obesesubjects,a weightreduction programme by diet and physical exercise in-

duced reductions of ICAM-1 and E-selectin, together

withbodyfat,after3months[104].Thebenefitoflifestyle

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

metabolicparameters 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- agonist fenofibrate induced a

reduction in serum adhesion molecules [108]. In non-

diabetic patients with coronary artery disease, the PPAR-

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 interactswith 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-B signalling [114]. Moreover,

ARBs lowered serum levels of CD40 ligand in patients

with hypertension, independently of BP reduction

[115]. In diabetic ischaemic patients, PPAR- activators

induced the same favourable effect [116].

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 andhumans 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- activators have beneficial effects on MCP-1, asdemonstrated 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- and

PPAR- 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

becomeuseful in the preventionof cardiovascular disease,

recentstudies with dual PPAR activators have cast doubts

on their clinical efficacy in cardiovascular prevention

compared with the original PPAR activators currentlymarketed. This being said, there is increasing evidence of

thepathophysiologicalroleplayedbyinflammationinthe

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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Received 4 September 2006/8 November 2006; accepted 22 November 2006

Published on the Internet 1 March 2007, doi:10.1042/CS20060247


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