Current Pharmaceutical Design, 2006, 12, 1623-1635 1623

Is Hypertension an Inflammatory Process?

Christopher J. Boos and Gregory Y.H. Lip*

Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham
B18 7QH, England, UK

Abstract: The risk factors for hypertension are only partly known, and accounts for the some of the deficiencies in current
primary prevention strategies and in the design of new drugs for the management of this common condition. Recently,
chronic low grade low-grade inflammation has been identified as an integral part in the pathogenesis of vascular disease.
Of note, inflammation may also be implicated in the development of hypertension, either as a primary or secondary event.
Indeed, several clinical studies have demonstrated increased numbers of well recognised pro-inflammatory markers, such
as high sensitive C-reactive protein (hsCRP), in patients with hypertension, even after adjustment for potential confound-
ing factors. Furthermore, elevated hsCRP levels have also been shown to be predictive for the development of hyperten-
sion in prehypertensive and normotensive patients. Pathophysiologically, inflammation has been implicated in both en-
dothelial (dys)function and arterial stiffness in hypertension, with reduced availability of nitric oxide (NO) being integral
to this process. Oxidative stress also appears to be a key feature in the reduced availability of NO and is aggravated by in-
creased circulating angiotensin II (Ang II). Importantly, there is some evidence that drugs commonly used in the man-
agement of hypertension, such as statins, angiotensin converting enzyme inhibitors and Ang II receptor blockers have
anti-inflammatory properties that can positively influence outcomes in patients with hypertension. The inflammatory state
in hypertension may pose a new therapeutic target for future drug design.
Key Words: Hypertension, inflammatory markers, inflammation, C-reactive protein, endothelium.

INTRODUCTION protein [hsCRP]) in patients with hypertension, even after

adjustment for potential confounding factors [11]. Further-
Hypertension is one of the most important risk factors for more, elevated hsCRP levels have also been shown to be
cardiovascular disease and has become an increasingly im-
predictive for the development of hypertension in prehyper-
portant contributor to the global health burden [1, 2]. Over-
tensive and normotensive patients [12, 13].
all, approximately 41.5% and 33.3% of English men and
women, are considered to be hypertensive, (defined as a The aim of this article is to present an overview of the
blood pressure above 140/90 mmHg), with the proportion available evidence supporting the putative link between in-
climbing far higher in persons > 60 years [3, 4]. Each year flammation and hypertension, and discuss the implications
there are 60,000 deaths due to stroke in the United Kingdom, for the drug treatment of hypertension.
with hypertension representing the most important risk factor
[3]. Consequently, the primary goal of antihypertensive ther- SEARCH STRATEGY
apy is the reduction of stroke.
We searched the following electronic data bases from
The risk factors for hypertension are only partly known, 1966 up to 23 rd May 2005: Pubmed, Medline, EMBASE and
and accounts for the some of the deficiencies in current pri- Cochrane Reviews. Given the enormity of this subject area,
mary prevention strategies and in the design of new drugs for we have highlighted five vascular markers in particular (with
the management of this common condition. Recently, brief mention of others) that are considered integral to the
chronic low-grade inflammation has been identified as an relationship between inflammation and hypertension. These
integral part in the pathogenesis of vascular disease. For ex- markers are high sensitivity hsCRP, Interleukin (IL)-6, IL-
ample, experimental data from atherosclerosis models have 1β, Tumour Necrosis Factor Alpha (TNF-α) and Angio-
confirmed the importance of chronic low-grade inflamma- tensin II (Ang II).
tion in its development and progression [5, 6]. Indeed, sev-
eral prospective clinical studies have shown that systemic INFLAMMATORY MARKERS
chronic low-grade inflammation is associated with an in-
creased risk of cardiovascular events and mortality [7-10]. Whilst there is a distinction between primary inflamma-
tory markers and vascular markers that may be indirectly
Among patients with hypertension, several clinical stud- involved in the inflammatory process (inflammatory sensi-
ies have demonstrated increased numbers of well recognised tive markers), the boundaries are somewhat blurred. Never-
pro-inflammatory markers (such as high sensitive C-reactive theless, there is an increasing evidence base to support a re-
lationship between elevation in vascular inflammatory mark-
*Address correspondence to this author at the Haemostasis, Thrombosis and
ers and hypertension [11].
Vascular Biology Unit, University Department of Medicine, City Hospital, Unfortunately most of the studies reporting an associa-
Birmingham B18 7QH, England; Tel: 0121 507 5080; Fax: 0121 554 4083;
E-mail: [Link]@[Link]
tion between these markers and hypertension are cross sec-

1381-6128/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.

1624 Current Pharmaceutical Design, 2006, Vol. 12, No. 13 Boos and Lip

tional in design and either did not make any adjustments or tolic blood pressure (BP) 120-139mmHg or diastolic BP 80-
only adjusted for a small number of potential confounders 89 mm Hg) when compared with normotensive subjects [12,
(see Tables 1 to 3). Many of these small studies were not 13, 50]. In a large cross sectional study, for example, King et
designed with the primary aim of testing the association of al. demonstrated that prehypertensive participants (BP [120-
inflammatory markers and hypertension. Taken together, 139] mm Hg and/or diastolic BP 80-89 mm Hg) had a higher
these studies represent a large cross section of differing prevalence of elevated hsCRP levels than normotensive
population groups and generally support the association be- subjects (27.4% vs. 19.8%; p<0.05) [13].
tween inflammation and hypertension.
Nonetheless, CRP is more than simply an inflammatory
marker of increased cardiovascular risk, as deposits of CRP
C-Reactive Protein (CRP)
have been demonstrated on immunohistochemical staining,
HsCRP has evolved as the most robust and reproduceable within the vascular wall of atherosclerotic plaques [51]. CRP
marker of vascular inflammation and is considered the pro- also stimulates the monocyte release of IL-1β, 1L-6 and
totypic downstream marker of inflammation [14, 15]. Tradi- TNF-α, as well as the expression of ICAM (intercellular
tional assays for CRP (using immuno-turbidometric meth- adhesion molecule)-1 and VCAM (vascular adhesion mole-
ods) had a sensitivity of about 5mg/L, only allowing for the cule)-1 by endothelial cells [52, 53]. This in turn leads to
detection of CRP in patients with a significant degree of in- stimulation of monocyte chemoattractant protein-1 (MCP-1)
flammation. In contrast, hsCRP (usually quantified by en- release, further amplifying the inflammatory process [54].
zyme linked immunoassays) allows for the accurate meas-
urement of CRP within the previously quantified normal In addition, CRP potently down-regulates endothelial
nitric oxide (NO) synthase (eNOS) transcription in endothe-
range (<5mg/L) in apparently healthy patients, who are at
lial cells and destabilizes eNOS mRNA, with resultant de-
increased future cardiovascular risk.
creases in both basal and stimulated NO release [54]. This
Indeed, evidence has confirmed a consistent relationship reduction in available NO is felt to be a critical step in the
between baseline hsCRP levels and the risk of future cardio- development of atherosclerosis, hypertension and vascular
vascular events (stroke, peripheral vascular disease, sudden events [55]. In addition, CRP has been shown to decrease
cardiac death, atrial fibrillation, plaque rupture and recurrent eNOS mRNA, protein abundance and enzyme activity in
ischaemia and myocardial infarction) [16-18]. For example human aortic endothelial cells [54, 56]. It is hypothesized
among 1157 patients from the original CAPTURE trial pre- that this process leads to impaired endothelial dependent
senting with refractory unstable angina, hsCRP was an inde- relaxation and subsequent development of hypertension.
pendent predictor of death or myocardial infarction at the
four year follow up [19, 20] CRP activates the complement pathway and induces cir-
culating monocytes to express tissue factor, a potent proco-
The evidence to support an independent association be- agulant factor [57]. Since CRP production by hepatocytes is
tween hsCRP and hypertension is also overwhelming, and regulated by proinflammatory cytokines, such as IL-6, IL-1β
far stronger than for any other studied inflammatory marker and TNF-α, it is highly unlikely that one inflammatory
(see Table 1) [21-45]. In contrast, published data negating marker per se would fully reflect the complexity of inflam-
this association are derived from only four studies, which mation and its apparent association with hypertension. In
have included low numbers of hypertensive patients (Table addition, the effect of one cytokine on blood pressure is
1) [46-49]. likely to be confounded by the effects of a great many other
The relationship between blood pressure and CRP ap- cytokines.
pears graded and continuous. For example, Sesso et al. dem- Some studies have examined the inter-relationships of the
onstrated during the follow up of 20,525 normotensive different inflammatory markers in hypertension. For exam-
women that the relative risk of developing hypertension from ple, Bautista et al. [46] examined the cross-sectional rela-
the lowest to the highest quartiles of baseline hsCRP were tionship between IL-6, TNF-α, and hsCRP and hypertension
1.00, 1.25 (95% CI, 1.14-1.40), 1.51 (95% CI, 1.35-1.68), in a random sample of 196 healthy subjects and showed that
1.90 (95% CI, 1.72-2.11), and 2.50 (95% CI, 2.27-2.75) (lin- after adjusting for other risk factors, IL-6 and TNF-α, hsCRP
ear trend p < .001) [36]. In addition, elevated hsCRP ap- were not significantly associated with hypertension. Whilst
peared to be predictive for the development of future hyper- this was a relatively small study and only include 79 hyper-
tension in apparently normotensive individuals, which might tensive patients, it is the only study to date to specifically
suggest that inflammation even precedes the subsequent de- analyse the potentially confounding relationship between
velopment of hypertension [32]. However, it is unknown several inflammatory markers and hypertension.
whether targeting normotensive patients with elevated
hsCRP, for the primary prevention of hypertension is feasi- Interleukin 6 and Interleukin-1β
ble, efficacious or cost effective, although this remains a
potentially promising area of future research. IL-6 is a pleiotropic cytokine produced by T-cells,
macrophages, and endothelial cells that has many diverse
The relationship between elevated hsCRP and hyperten- physiological roles, including mediation of both pro-
sion is not exclusive to blood pressure within the so-called inflammatory responses and cyto-protective functions [58].
‘hypertensive range’. Several studies have recently provided
IL-6 stimulates the synthesis of several acute-phase reaction
further support to the inflammation/hypertension association
proteins, including CRP, Serum amyloid-A and fibrinogen,
by demonstrating higher hsCRP levels among patients with and counterregulates TNF-α and IL-1β [59]. It is also known
blood pressure in the ‘pre-hypertension’ stage (that is, sys-
Is Hypertension an Inflammatory Process? Current Pharmaceutical Design, 2006, Vol. 12, No. 13 1625

Table 1. Studies Demonstrating an Association Between Elevated Blood Pressure and CRP

Population Significant association

Author Year Sample size Adjusted for
Studied with CRP (p<0.05)

Koenig et al. [21] 1999 German 936 men HT None

Yudkin et al. [22] 1999 British 107 SBP/DBP Age, sex

Rohde et al. [23] 1999 US 1172 men HT Age

Doggen et al. [24] 2000 Netherlands 1206 SBP/DBP None

Margaglione et al. [25] 2000 Italian 1048 HT None

Ford and Giles [26] 2000 US 8850 men SBP Age, ethnicity, sex

Age, sex, ethnicity, smoking, BMI,

Festa et al. [27] 2000 US 1008 SBP/DBP
insulin sensitivity, age, waist size

Age, waist size, fibrinogen,

Yamada et al. [28] 2001 Japanese 6107 SBP
total cholesterol, physical activity

Age, sex, BMI, family history of hypertension,

Bautista et al. [29] 2001 Colombian 300 HT
fasting glycaemia, behaviour, alcohol consumption

Wong et al. [30] 2001 US 9684 SBP Cigarette smoking, age, BMI

HRT treatment, cholesterol, family history of MI,

Bermudez et al. [31] 2002 US 340 women SBP
diabetes, smoking status, exercise, alcohol use

Saito et al. [32] 2003 Japanese 908 SBP Univariate only

Cardiovascular risk factors,

Di Napoli et al. [33] 2003 Italian 535 SBP
demographic factors (not mentioned which)

BMI, age, smoking status, LDL cholesterol,

Blake et al. [34] 2003 US 15 215 women SBP, DBP
HDL cholesterol and diabetes

Age, sex, smoking status, BMI, lipid profile, trigly-

Schillaci et al. [35] 2003 Italian 135 SBP
cerides, heart rate, ambulatory and office blood pressure

Sesso et al. [36] 2003 US 20525 women SBP, DBP Coronary risk factors

Sung et al. [37] 2003 Korean 8347 Age, sex, fasting blood sugar, triglycerides, lipids, BMI

Ridker et al. [38] 2003 US 14 719 women HT None

Stuveling et al. [39] 2004 Netherlands 8592 MAP Waist size, age, cholesterol, smoking,

Yasmin et al. [40] 2004 British 427 MAP Age

Fredrikson et al. [41] 2004 Swedish 760 SBP Smoking, BMI

Age, total cholesterol, HDL,

Verma et al. [42] 2004 US 1154 male SBP/DBP
smoking, BMI

Sex, obesity, race, serum insulin level and

Bautista et al. [43] 2004 Greek 3042 SBP, DBP
family history of coronary heart disease

Age, body mass index, blood lipids,

Chrysohoou et al. [12] 2004 Greek 1188 Prehypertension
glucose, food groups consumed

Prehypertensiona Age, sex, race, smoking, body mass index,

King et al. [13] 2004 US 16,966
SBP/DBP exercise, diabetes, and medication usage

Stumpf et al. [44] 2005 German 30 MAP Yes, but not stated which

Vaselka et al. [45] 2005 Czech 490 HT Age, MI, smoking, DM

HT, hypertension; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial blood pressure; PP, pulse pressure; HDL, high density lipoprotein; LDL, low
density lipoprotein; MI, myocardial infarction, HRT, hormone replacement therapy; BMI, body mass index; a pre-hypertension defined as SBP of 120-139mmHg and DBP BP of 80 –
89 mmHg.
1626 Current Pharmaceutical Design, 2006, Vol. 12, No. 13 Boos and Lip

that IL-6 prolongs endothelial dysfunction, which may in activation of the immune system, and its release is stimulated
turn lead to increasing peripheral vascular resistance and by several factors, including IL-1β and bacterial endotoxin
consequent hypertension [60, 61]. However, the data linking [77, 78]. Of note, intra-arterial TNF-α has been shown to
increased IL-6 to hypertension is less convincing than that causes an acute local vascular inflammation that is associ-
for CRP, and of the published studies, [6] have reported a ated with impaired endothelium-dependent relaxation [79].
positive association between IL-6 and hypertension [22, 44,
There are nine studies to date that have looked into the
46, 62-64] with 3 reporting negative results (Table 2) [47, potential association between increasing TNF-α and hyper-
61, 65]. tension (Table 3). Seven reported a positive association with
IL-1β is a proinflammatory cytokine produced by acti- TNF-α and hypertension [12, 22, 44, 46, 65, 81, 82] with
vated macrophages, endothelial Cells, B-Cells, and fibroblast two reporting negative results [47, 80]. Of interest, the Attica
cells [66, 67]. Data supporting the association of IL-1β with study demonstrated an association between elevated TNF-α
hypertension is derived from only three small studies, of less levels and prehypertension, even after correcting for multiple
than 120 patients (Table 2) [68-70]. In only one of these comparisons and adjusting for age, body mass index, blood
three studies were adjustments made for potential con- lipids, glucose, food groups consumed, and other potential
founders (and only for lipids), significantly weakening the confounders [12]. There is also evidence to support the syn-
strength of the identified association [69]. thesis of TNF-α in adipose tissue [83]. This may contribute
to both the maintenance of a chronic low-grade inflamma-
There is emerging data from several gene studies ad- tory state in obese patients and to the associated comorbid-
dressing whether polymorphisms in the IL-6 and IL-1β gene ities, such as hypertension [83-85]. In one study of 368 indi-
might predispose to hypertension. Unfortunately the results viduals, the ratio of soluble TNF-α receptors (sTNFR2/
have been largely conflicting, and no firm conclusions can sTNFR1, a surrogate for TNF-α activation), correlated posi-
be made from the currently available data [71-74]. tively with both systolic and diastolic blood pressure, and
reduction in blood pressure equated with a fall in this ratio
Tumour Necrosis Factor Alpha (TNF-α) [86]
TNF-α is a 185 amino acid glycoprotein peptide hor- The precise mechanisms by which TNF-α influences
mone that is synthesized mainly by monocytes and macro- hypertension are uncertain, but TNF-α decreases eNOS
phages [75, 76]. TNF-α plays a significant role in the initial mRNA levels by increasing the rate of mRNA degradation

Table 2. Studies Reporting on Possible Association Between IL-6, IL-1β and High Blood Pressure

Population Significant association with

Author Year Sample size Adjusted for
Studied inflammatory marker (p<0.05)

IL-6

Mendall et al. [47] 1997 British 198 men No Age, BMI, smoking, occupation, alcohol

Rifae et al. [61] 1999 US 100 men No None

Yudkin et al. [22] 1999 British 107 SBP/ DBP Age and sex

Ridker et al. [62] 2000 British 202 SBP/ DBP None

Age, AMI, BMI, parent AMI, diabetes, use of alcohol,

Chae et al. [63] 2001 US 508 men SBP/DBP
aspirin use, smoking, cholesterol, physical activity

Fernandez et al. [64] 2001 Spanish 226 SBP/ DBP BMI

Furomoto et al. [65] 2002 Japanese 119 No Age, sex

Age, sex, BMI, family history of HBP,

Bautista et al. [46] 2005 US 196 SBP/ DBP
inflammatory markers (CRP, TNF-α)

Stumpf [44] 2005 German 30 MAP Yes, but variables not listed

IL-1β

Dalekos et al. [68] 1996 Greek 114 SBP/DBP Nil

Zhao et al. [69] 2004 Chinese 36 SBP/DBP Lipids

Dalekos et al. [70] 1997 Greek 94 SBP/DBP Nil

SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; HBP, high blood pressure; CRP, C reactive protein; TNF, tumour necrosis factor.
Is Hypertension an Inflammatory Process? Current Pharmaceutical Design, 2006, Vol. 12, No. 13 1627

Table 3. Studies Reporting on Possible Association Between TNF-α and High Blood Pressure

Population Significant association

Author Year Sample size Adjusted for
Studied with TNF-α (p<0.05)

Age, BMI, occupation, social class,

Mendall et al. [47] 1997 English 198 men No
smoking, alcohol use

Yudkin et al. [22] 1999 English 107 SBP/ DBP Age and sex

Sheu et al. [80] 2000 Taiwanese 170 No None

Ito et al. [81] 2001 Japanese 82 women SBP, not DBP Age and menopause

Fernandez et al. [82] 2002 Spanish 370 SBP/DBP Age and BMI

Furumoto et al. [65] 2002 Japanese 119 HT Age and sex

Age, body mass index, blood lipids,

Chrysohoou et al. [12] 2004 Greek 3042 Prehypertension
glucose, food groups consumed

Age, sex, BMI, family history,

Bautista et al. [46] 2005 US 196 HBP
inflammatory markers (CRP, TNF-α)

Stumpf [44] 2005 German 30 HT Yes, but variables not listed

SBP, systolic blood pressure; DBP, diastolic blood pressure; HT, hypertension.

and shortening its half-leading to a reduction in NO diators, including IL-6, MCP -1 and nuclear factor-κB and
bioavailability [87, 88]. Of note, a common polymorphism in nuclear factor-alpha and VCAM-1 on endothelial cells [96,
the promoter region (-308 G/A) of the TNF-α gene is associ- 98-103]. Indeed, MCP -1 is integral to the homing of in-
ated with elevated systolic blood pressure [89]. flammatory cells into cardiovascular tissue, whilst the in-
duction of the inflammatory response is regulated by the
In summary, there is compelling evidence to link an in-
crease in several known proinflammatory cytokines and hy- transcription of nuclear factor-kappaB [104]. Furthermore,
human monocytes are known to possess Ang II receptors and
pertension. The relationship between these markers and hy-
can can be activated by the peptide [105].
pertension, is most consistent for hsCRP, but has also been
shown for IL-6, IL1β and TNF−α albeit to a lesser extent,
Other Vascular Markers
which may relate in part to greater difficulty in performing
these later assay. The list of additional vascular markers involved in in-
flammation, and found to be positively associated with hy-
Angiotensin II pertension is ever increasing. We have highlighted some of
these in Table 4 [106-121]. One caveat is that there may be a
Hypertension is associated with structural alterations of
degree of reporting bias in the literature, with a tendency to
resistance arteries, a process known as remodelling (with an
mainly publish studies reporting a positive association be-
increased media-to-lumen ratio) [90, 91]. At the cellular
tween inflammation and blood pressure.
level, vascular remodelling involves changes in vascular
smooth muscle cell growth, cell migration, inflammation and Abnormalities of the coagulation-fibrinolytic system (in-
fibrosis – all these processes are mediated via multiple fac- creased fibrin D-dimer and plasminogen activator inhibitor-
tors, of which Ang II appears to be one of the most important 1) and platelet activation (increased P-selectin, and β-
in hypertension [92, 93]. thromboglobulin) occur as part of the inflammatory process
Ang II is a regulatory hormone formed locally in several of hypertension and may be one of the reasons for the in-
creased thrombotic risk with hypertension [120, 122, 123].
tissues (including the vascular wall) with a key role in BP
control, by stimulating vascular smooth muscle constriction, Indeed, the arterial walls in hypertension are exposed to the
aldosterone release from the adrenal cortex, and sodium re- flow of blood under high pressures, but yet the complications
absorption from the renal tubule [94]. Experimental studies of hypertension, such as myocardial infarction or stroke are
paradoxically thrombotic rather than haemorrhagic – the so-
have revealed that Ang II possesses several proinflammatory
called “thrombotic paradox of hypertension” or “Birming-
properties and Ang II may act locally as a chemokine and
inflammatory molecule [95, 96]. For example, Ang II has ham paradox” of hypertension [124].
been shown to upregulate vascular endothelial growth factor
(VEGF) in the aortic wall, leading to monocyte infiltration INFLAMMATION AS AN INITIATOR OF HYPER-
TENSION
and remodelling [97].
Ang II can also illicit the production of reactive oxygen One of the great difficulties with the association between
species (ROS) and up-regulate other proinflammatory me- inflammation and hypertension is the so called ‘chicken and
1628 Current Pharmaceutical Design, 2006, Vol. 12, No. 13 Boos and Lip

the egg phenomenon’. It is now well known that certain ab- in Lyon hypertensive rats [137]. However, hypertension it-
normalities of endothelial function can lead to hypertension self has been shown to lead to the activation of nuclear tran-
and that hypertension itself can negatively alter endothelial scription factor NF-κB, which induces the transcription of a
function [125-127]. At the same time, it is not known large range of inflammatory genes, such as those coding IL-
whether inflammation is a cause or effect of hypertension. 6, MCP-1, VCAM-1 and ICAM-1 [138, 139].
In the clinical setting, inflammation can cause endothelial
Table 4. Other Inflammation Sensitive Vascular Markers dysfunction with consequent alterations in the synthesis and
that have found to be Associated with Hypertension degradation of vasodilating and vasoconstricting factors
[140, 141]. At the same time, the association between endo-
Acute phase reactants thelial function and the development of hypertension has
Fibrinogen [106] been demonstrated by the increased vascular markers of en-
dothelial damage/dysfunction (for example, von Willebrand
Soluble Adhesion molecules factor, E-selectin, soluble thrombomodulin), reduced flow-
VCAM-1, ICAM [107-110] mediated dilation and impaired skin blood flow response
P-selectin, E-selectin [110-113] using laser Doppler flowmetry [142-144]. Endothelial dys-
Interleukin-15 [114,115]
function may thus represent the platform on which chronic
inflammation might lead to the development of hypertension.
Leukocytes – neutrophils and monocytes [12,70]
β-thromboglobulin [116] INFLAMMATION AND ARTERIAL STIFFNESS
Markers of Coagulation system activation Another avenue of support for inflammation and hyper-
D-dimer, PAI-1 [106] tension hypothesis is the finding that inflammation can lead
Endothelin 1 [107, 110, 117-119]
to increased arterial stiffness [144-150]. Indeed, increased
arterial stiffness is an independent determinant of cardiovas-
VEGF [120, 121] cular risk and can lead to hypertension, due to changes in
VWF [107, 111, 120] mechanical stress in the arterial wall and an overall reduction
Amyloid-a [12] in shear stress [151-153].
MMP-9, MMP-2 [40]
CD-40 Ligand [121]
A number of methods for assessing arterial stiffness have
evolved and include parameters such as arterial pulse wave
TNF-α , tumour necrosis factor alpha; IL, Interleukin; Hs-CRP, highly selective C- velocity (the speed at which the forward pressure is trans-
reactive protein; VCAM, vascular cell adhesion molecule; ICAM, intercellular adhe- mitted from the aorta through the vascular tree), ultrasound,
sion molecule; P-selectin, platelet derived; E-selectin, endothelial derived selectin;
PAI, Plaminogen activator inhibitor; VEGF, vascular endothelial growth factor; MMP,
or arterial waveform analysis (either by systolic or diastolic
matrix metalloproteinase. pulse contour analysis) [154]. Of note, there is a significant
relationship between hsCRP and stiffness of large arteries
The adventitia, previously considered a rather bland [150, 155]. Elevations in hsCRP levels have been associated
physical barrier, is now known to be an important source of with reduced arterial elasticity and increased arterial pulse
oxygen free radicals potentially participating in the patho- wave velocity, both surrogate markers for developing hy-
physiology of hypertension [128]. Increased numbers of in- pertension and atherosclerosis [156-158].
flammatory cells have been identified in the adventitia of
hypertensive rats [129]. Also, in spontaneously hypertensive INFLAMMATION, ENDOTHELIAL DYSFUNCTION
rat models it has been demonstrated that there are increased AND HIGH BLOOD PRESSURE
numbers of activated monocytes, increased monocyte and The precise mechanism(s) by which inflammation leads
lymphocyte counts, and increased monocyte adhesion to to hypertension is unknown. However our understanding of
endothelial cells [130-132]. In a key paper, Dorffels et al. this highly complex process has increased in recent years, by
were able to demonstrate increased baseline secretion of IL- recognising the fundamental role of the endothelium in vas-
1β and TNF-α from peripheral blood monocytes among hy- cular homeostasis [159]. Nonetheless, a detailed treatise on
pertensive versus non hypertensive patients [133]. Further- the endothelium in hypertension is beyond the scope of this
more, the authors noted even higher cytokine secretion overview, and has been the subject of recent reviews [124,
among hypertensive patients stimulated with lipopolysaccha- 160].
ride (a known monocyte stimulator) than compared with
control, indicating the presence of preactivated peripheral Under physiological conditions, there is a balanced re-
blood monocytes in hypertensive patients [133]. lease of relaxing and contracting factors. Endothelium-
dependent vasodilation is regulated primarily by NO, but
Several immunopathogenic mechanisms may be central also by an endothelium-derived hyperpolarizing factor,
to the pathogenesis of hypertension. There is evidence in prostacyclin (PGI 2), as well as acetylcholine and bradykinin
both human and animal models linking hypertension to al- acting on specific receptors, and finally, by mechanical
terations of both humoral and cellular immunity, which forces, such as shear stress [124, 160]. Endothelium-derived
might suggest a primary role for inflammation in the causa- contracting factors include endothelin-1, vasoconscrictor
tion of hypertension [134-136]. For example, the in vivo ad- prostanoids (thromboxane A2 and prostaglandin H2), ang II
ministration of silica, which is selectively toxic to mono- and superoxide anions [161]. Hypertension is caused by an
cytes, has been shown to reduce the degree of hypertension imbalance between the above mentioned endothelial derived
Is Hypertension an Inflammatory Process? Current Pharmaceutical Design, 2006, Vol. 12, No. 13 1629

vasoactive substances, resulting from either an increase in In Fig. 1, we present a simplistic mechanistic interpreta-
vasoconstrictor substances or decrease in vasodilator sub- tion of how chronic inflammation might lead to hypertension
stances [161, 162]. using currently available evidence.
Under normal conditions NO acts locally to prevent EVIDENCE FROM THERAPEUTIC TRIALS
platelet and leucocyte aggregation and inhibits vascular
smooth muscle cell proliferation. Hence, reduced NO avail- The data presented, thus far, offers compelling evidence
ability can radically shift the balance in favour of a to support an association between inflammation and hyper-
prothrombotic and inflammatory state, with increased vas- tension. However, there is accumulating data from the cur-
cular smooth muscle proliferation [160, 163]. We know that rent medical literature to suggest that it is not only blood
inflammation leads to endothelial dysfunction and down- pressure reduction per se but the way in which blood pres-
regulation of eNOS, strongly suggesting the importance of sure is lowered that is most the important factor in hyperten-
NO as a key factor linking inflammation to hypertension and sion treatment [183]. If inflammation is truly linked to hy-
vice versa [164-166]. pertension, then it would be reasonable to assume that drugs
with anti-inflammatory actions might be able to arrest in-
INFLAMMATION AND OXIDATIVE STRESS IN flammation, improve endothelial function and lower blood
HYPERTENSION pressure in patients with hypertension. In addition, these
agents might thus be able to positively influence cardiovas-
ROS including superoxide (*O2-), hydrogen peroxide cular outcomes over and above that of ‘pure’ hypotensive
(H2O2), and hydroxyl anion (OH-), and reactive nitrogen agents.
species, such as NO and peroxynitrite (ONOO-), are biologi-
cally important O2 derivatives that are increasingly recog- This hypothesis has been supported by clinical trial data
nized to be important in vascular biology through their oxi- demonstrating that reduced Ang II generation by either ACE
dation/reduction (redox) potential [167]. All vascular cell inhibition or Ang II receptor blockade significantly improves
types (endothelial cells, vascular smooth muscle cells, and endothelial function and lessens vascular micro-inflamma-
adventitial fibroblasts) produce ROS. The sources of these tion in patients with essential hypertension [184-189]. For
ROS include cell membrane-associated NAD(P)H oxidase, example, in the recently published EUropean Trial on Olme-
eNOS (via NOS uncoupling), cyclooxygenase, lipoxygenase sartan and Pravastatin in Inflammation and Atherosclerosis
and xanthine oxidase [168-170]. Physiological ROS are pro- (EUROPIA), Angiotensin II receptor blockade significantly
duced in a controlled manner at low concentrations and reduced vascular microinflammation (hsCRP, IL-6, TNF-α)
function as signalling molecules to maintain vascular integ- in patients with essential hypertension [184].
rity by regulating vascular function, modulating cell growth, It is now well recognised that in addition to their choles-
apoptosis/anoikis, migration, inflammation, secretion, and terol lowering effects, HMG Co-enzyme A inhibitors (‘stat-
extracellular matrix protein production [171]. ins’) possess anti-inflammatory properties and can dramati-
cally improve endothelial function. For example, statin ther-
ROS have an important role in the inactivation of NO
[168]. Under pathological conditions there an imbalance in apy has lead to significant reductions in levels of pro-
redox state where pro-oxidants overwhelm anti-oxidant ca- inflammatory cytokines (TNF-α, IL-1 and IL-6) as well as in
ICAM-1 and CRP [190-192]. Recent data also demonstrate
pacity leading to oxidative stress, endothelial dysfunction
that statins inhibit the induction of the major histocompati-
and reduced NO availability (with O2- binding to NO to form
bility (MHC) class II expression by interferon-gamma,
ONOO-) [172, 173]. This reduced NO availability leads to
leading to repression of MHC II-mediated T-cell activation
several simultaneous processes which may culminate in vas-
[193]. Furthermore, statins inhibit the expression of specific
cular damage and hypertension: (i) vascular contractility is
cell surface receptors on monocytes, adhesion molecules and
increased; (ii) inflammation with increased cytokine produc-
also integrin-dependent leucocyte adhesion [194].
tion (e.g. TNF-α, IL-6 and subsequently CRP) and upregu-
lation of adhesion molecules (such as VCAM-1 and ICAM- Statins have also been shown to improve arterial stiffness
1) leading to monocyte attraction to the endothelial mono- in hypertensive patients [195]. For example, in one study of
layer; (iii) lipid peroxidation; and (iv) increased deposits of subjects with moderate hypercholesterolemia and hyperten-
extracellular matrix proteins [171, 174-178]. sion, treatment with pravastatin decreased mean systolic,
diastolic, and pulse pressures [196]. Similarly, Magen et al.
ROS have been shown to upregulate protoconcogene and [197] were able to demonstrate that atorvastatin 20 mg/day
proinflammatory gene expression [171]. Increased NAD(P)H
led to improved blood pressure control in patients with re-
driven O2- generation as well as polymorphisms in NAD(P)H
sistant hypertension and dyslipidaemia. However, there is
oxidase have been identified in spontaneously hypertensive still a paucity of data to support the hypothetical blood pres-
rats [179]. Poylmorphisms in the NAD(P)H promoter gene sure lowering effects of stain therapy. However, current pre-
with consequent reduced NO production has also been iden-
liminary data would suggest that the observed hypotensive
tified in human hypertensive models [180, 181]. In a key
effects might relate in part to intrinsic anti-inflammatory
paper, Yasanari et al. [182]. were able to show that com- properties, as well as improved endothelial dysfunction
pared with normotensives, hypertension was associated with
[198].
increased oxidative stress of peripheral blood polymor-
phonuclear leukocytes and mononuclear cells, and that the CONCLUSION
higher the blood pressure, the greater the degree of oxidative
stress. There is increasing evidence to support the role of
chronic low-grade inflammation in a number of previously
1630 Current Pharmaceutical Design, 2006, Vol. 12, No. 13 Boos and Lip

Fig. (1). The possible role of inflammation in the development of hypertension.

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