Send Orders for Reprints to [email protected] 672 Medicinal Chemistry, 2014, 10, 672-681 Inflammation Markers in Essential Hypertension

Dimitrios Tsounis1,*, Georgios Bouras1, Georgios Giannopoulos2, Charalampos Papadimitriou3, Dimitrios Alexopoulos4 and Spyridon Deftereos2

1Department of Cardiology, Athens General Hospital “G. Gennimatas”, Athens, Greece; 2Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA; 3Hellenic Center for Disease Control and Prevention, Athens, Greece; 4Department of Cardiology, Patras University Hospital, Rion, Greece

Abstract: Essential hypertension is a common health disorder with uncertain etiology and unclear pathophysiology. There is evidence that various systems interact in uncertain ways and mechanisms to cause hypertension. It is also well known that inflammation is a key feature in the initiation, progression and clinical implication of several cardiovascular diseases. Recently, it has become evident that the immune system and inflammatory response are also essential in the pathogenesis of hypertension. Many inflammation markers such as CRP, cytokines, and adhesion molecules have been found elevated in hypertensive patients supporting the role of inflammation in the pathogenesis of hypertension. Also, in normotensive individuals, these markers have been associated with the risk of developing hypertension, whereas in hypertensive patients they have been associated with target organ damage as well as with the risk for future cardiovascular events. Thus, understanding the role of inflammation in hypertension provides new insights for novel therapeutic approaches, targeting inflammation for the treatment of hypertension and its complications.

Keywords: Adhesion molecules, biomarkers, CRP, cytokines, hypertension, inflammation, target organ damage, treatment.

INTRODUCTION between inflammatory cells, such as macrophages and T lymphocytes, leading to increased expression of adhesion Essential hypertension is a common health disorder with molecules, cytokines, matrix metalloproteinases and growth high prevalence reaching 30-45% of the general population factors (Fig. 1) [7, 8]. These molecules guide the adaptive among European countries and increasing with age, while its immune response and the migration of the immune cells to etiology and pathophysiology still remain undefined and target tissues and promote the binding, rolling and infiltra- unclear. In 90-95% of the patients hypertension can be clas- tion of the immune cells into vascular wall and translocation sified as “primary/essential”, with heterogeneous, multifac- to end organs. Inflammatory response involves not only the torial and elusive etiology and only in 5-10% of them the perivascular adipose tissue and vascular wall, leading to re- cause is a known and identifiable factor (secondary hyper- modeling and impaired vascular function but also the heart tension) [1, 2]. Hypertension is an important risk factor for (causing vasoconstriction and ischemia), the kidneys (caus- cardiovascular disease morbidity and mortality and an im- ing renal vasoconstriction and renal injury) and the central portant public health challenge due to the enormous health nervous system, as animal and human studies have shown and economic burden, despite the widely available anti- [9-13]. hypertensive treatments [3, 4]. Studies have also suggested that hypertension exerts pro- Various systems interact in uncertain ways to cause hy- inflammatory actions through increased expression of sev- pertension and three components, -vascular dysfunction, eral inflammatory mediators including endothelin-1 and an- renal impairment, and altered sympathetic outflow- have giotensin. Apart from angiotensin II association with vaso- been found to play a pivotal role in the development and constriction and salt and fluid homeostasis, its role is equally maintenance of elevated blood pressure [5]. Recently, in- important in the vascular inflammation and oxidative stress creasing evidence suggests that the immune system and in- [14, 15]. Specifically, angiotensin II increases pro-inflamm- flammatory response are also essential in the pathogenesis of atory nuclear factor-kappa-B-dependent gene expression and hypertension [6]. stimulates the expression of various inflammatory molecules Inflammatory process in hypertension is a complex re- such as chemokines, cytokines and adhesion molecules and sponse of the immune system that consists of interactions through activating nicotinamide-adenine dinucleotide phos- phate (NADPH) oxidase, promotes the generation of reactive oxygen species [10,16]. Consequently, the detection and mon- *Address correspondence to this author at the Department of Cardiology, Athens General Hospital “G. Gennimatas” Mesogeion 154, 11527, Athens, itoring of inflammation markers that are involved in the pa- Greece; Tel: ++302107768336; Fax: ++302107768336; thogenesis of hypertension are of great scientific interest for E-mail: [email protected] the diagnosis and prognosis of cardiovascular disease [17, 18].

1875-6638/14 $58.00+.00 © 2014 Bentham Science Publishers Inflammation Markers in Essential Hypertension Medicinal Chemistry, 2014, Vol. 10, No. 7 673

Normotensive Conditions!

ILIL-10 10! Vascular! TNF-T !" Inflammation! TGFTGF#"

Immune suppressive Foxp3+! phenotype! Hypertension, salt, ET-1, Ang II, Aldosterone!

%&'()")" INF-INF $" Vascular! *+,-" (&'()"" Inflammation! TNF-T !" ILIL-17 17! ! Pro-inflammatory! phenotype! Fig. (1). In normotensive conditions, when innate immunity is not activated, macrophages are not stimulated and will not produce tumour necrosis factor (TNF) !. Accordingly, antigen-presenting cells (APCs, dendritic cells [DCs]) have an anti-inflammatory or immune suppres- sant phenotype, and stimulate the commmitment of naive T lympocytes to the T regulatory cell (Treg) lineage. These T lymphocytes will produce the anti-inflammatory interleukin (IL)-10 and transforming growth factor (TGF) ", which will suppress vascular, cardiac or renal inflammation. As a result of stimulation of damage-activated molecular pattern (DAMP) receptors, APC or DCs adopt a pro-inflammatory phenotype, migrate to secondary lymphoid organs and stimulate the maturation of T effector lymphocytes such as T helper (Th)1 which pro- duce interferon (IFN) # and IL-6, or Th17 which produce IL-17, leading to a vascular, cardiac, or renal inflammatory response. DAMPs stimulation could be a consequence for example of blood pressure elevation, or stimulation of pathogen-activated molecular pattern recep- tors, the latter in response to forms of low-grade infection, or other conditions resulting in elevated TNF-!, a consequence of genetic predis- position, high salt intake, increased endothelin (ET)-1, or activation of the renin-angiotensin II (Ang II)-aldosterone system. Formation of neoantigens, could also be a cause of activation of T effector lymphocytes leading to a role in low-grade inflammation in cardiovascular dis- ease. HTN: hypertension; Foxp3: forkhead box P3; PAMP: pathogen-activated molecular pattern. (Adapted with permission from Schiffrin E. L. The immune system: role in hypertension. Can. J. Cardiol. 2013 , 29,543-8).

In this review, we will summarize the evidence of the Several epidemiological studies have examined the rela- pathophysiological connection between inflammation and tionship between CRP levels and cardiovascular risk in indi- essential hypertension focusing on traditional and novel in- viduals without known cardiovascular disease and have flammatory markers and the new insights for novel anti- shown CRP to be an independent cardiovascular risk factor inflammatory therapeutic approaches for the treatment of [21]. hypertension and its complications. Particularly, in a recent meta-analysis of 54 prospective CRP studies including individuals without history of cardiovascu- lar disease, CRP exhibited a strong log-linear relation with C-reactive protein (CRP) is a 115-kDa pentamer synthe- the risks of coronary artery disease (CAD), ischemic stroke sized under the control of interleukin (IL)-6, in hepatocytes, and vascular and non-vascular mortality [22]. although it can also be produced extrahepatically in kidney and adipose tissue, in the setting of innate, non-specific im- Several cross-sectional and prospective studies have mune response to several pathophysiological conditions such shown, after adjustment for potential confounders,that CRP as inflammation, infection, cell damage, apoptosis, and neo- is increased in hypertensive patients, and its levels predict plasms [19]. the onset of hypertension[23-30]. Batista et al. were the first to report higher CRP levels in hypertensive patients than in Despite being an inflammatory marker, CRP may also normotensive, independently of the influence of several CRP play an important role in vascular inflammation as a pro- covariates such as age, body mass index (BMI), fasting gly- moter of pro-inflammatory and pro-atherogenic process. caemia, sedentary behavior, alcohol consumption and family Additionally, it is the most stable inflammation marker with history of hypertension [23]. Furthermore, Sesso et al. in a no circadian variations and therefore the most studied in car- cohort study regarding females from the Women’s Health diovascular disease. Specifically, CRP has various effects on Study reported that after a median follow-up period of 7.8 the vascular endothelium including expression of adhesion years, about 26.1% of the enrolled women developed hyper- molecules, chemokines and monocyte chemotactic protein-1 tension and CRP was independently associated with an in- (MCP-1), plasminogen activator inhibitor-1 (PAI-1), matrix creased risk of developing hypertension, even in those metalloproteinases and endothelin-1, whereas it decreases women with very low initial systolic and diastolic blood the production of nitric oxide (NO), prostacyclin and tissue pressure or without traditional cardiovascular risk factors plasminogen activator (tPA) [19, 20]. [28]. More recently, Kong et al. demonstrated that CRP lev- 674 Medicinal Chemistry, 2014, Vol. 10, No. 7 Tsounis et al. els were independently associated with the development of [58]. Finally, Ozdogan et al. reported that patients with hypertension in the follow-up study [24]. white-coat hypertension also have higher CRP levels than normotensive patients and suggested that these patients Additionally, blood pressure variability and its diurnal might be of increased cardiovascular risk [59]. variations also seem to be associated with inflammation. Especially, patients with greater blood pressure variability and non-dipping nighttime pattern demonstrate increased CYTOKINES CRP levels [31, 32]. Moreover, higher CRP levels are also Cytokines represent a diverse group of various soluble present in pre-hypertensive patients and in hypertensive pa- short-acting molecules (proteins, glycoproteins and peptides) tients’ offsprings, suggesting that low-grade inflammation, at exerting a wide range of actions. They are produced and se- least in some circumstances, might precede blood pressure creted in extremely low concentrations by a variety of im- elevations [33-35]. mune (macrophages, T lymphocytes), vascular cells and adi- As for pediatric populations, cross-sectional data for pocytes, activate specific receptors and modulate the func- children and adolescents (8-17 years old) from the National tion of many cells and tissues including immune, vascular Health and Nutrition Survey have also shown that children smooth muscle and endothelial cells as well as extracellular with higher (>3 mg/l) CRP levels had higher systolic blood matrix [58, 59]. Many individual cytokines are pleiotropic pressure compared to those with lower levels (!3 mg/l), encompassing multiple actions, while others exert overlap- while in another study that evaluated the profile of inflam- ping actions. They are primarily involved in host response to matory mediators in children with primary hypertension, disease or infection and most of them are not expressed un- hypertensive children had greater CRP, MIP-1" (Macro- less specifically stimulated by a noxious event [62]. phage Inflammatory Protein-1") and RANTES (Regulated They are classified into the following categories: Tumor on Activation Normally T-cell Expressed and Secreted) Necrosis Factors (TNFs), Interleukins (ILs), Lymphokines levels than controls and CRP levels were correlated with and Monokines, Interferons (IFNs), Colony stimulating fac- number of metabolic syndrome criteria, body mass index, tors (CSFs), Transforming growth factors (TGFs), Bone carotid intima-media thickness, left ventricular mass and morphogenetic proteins (BMPs) and Chemokines. Some markers of oxidative stress [36, 37]. cytokines, called pro-inflammatory cytokines, are produced Likewise, CRP levels have been associated with target- predominately by activated macrophages and promote in- organ damage. Many studies have reported an association flammation by acting as endogenous pyrogens, chemoattrac- between CRP levels and microalbuminuria in hypertensive tants or by up-regulating inflammatory reaction, whereas patients [34, 40-48]. Such relation has been described even others suppress the activity of pro-inflammatory cytokines in pre-hypertension, in a study from Navarro-Gonzalez et al., and are involved in the down-regulation of inflammatory where high sensitivity CRP (hsCRP) was demonstrated to be response exhibiting anti-inflammatory action (anti- independently correlated with urinary albumin excretion and inflammatory cytokines) [61, 63]. an independent risk factor for microalbuminuria. The latter The importance of specific cytokines in cardiovascular implies that inflammatory processes might be part of the disease and hypertension has been demonstrated in a number pathogenesis of early vascular target organ damage in pre- of recent studies [64]. TNF-# and IL-6 are the most studied hypertensive individuals [34]. cytokines in hypertension. Bautista et al. reported that raised Furthermore, left ventricular hypertrophy (LVH) has also TNF-# and IL-6 levels were independent risk factors for high been related to CRP levels according to studies from Assadi blood pressure in apparently healthy subjects after adjust- et al. in children and adolescents with essential hypertension ment for age, sex, BMI, family history of hypertension and [49], while Tsai et al. reported significant increase in hsCRP the levels of the other inflammatory markers [65]. among adult patients without LVH, with LVH but not prote- Furthermore, in a study from Mauno et al. baseline levels inuria and with both LVH and proteinuria [50]. Moreover, in of IL-1b and IL-1ra were significantly higher in those indi- a study from Turak et al. hsCRP levels were significantly viduals that developed hypertension during the follow up, related to impaired echocardiographic indices of left ven- providing evidence that pro-inflammation might precede tricular diastolic function, independent from other factors hypertension [66]. Similarly Navarro-Gonzalez et al. re- including age, waist circumference and 24-h systolic blood vealed that plasma hsCRP levels and urinary TNF-# excre- pressure [51]. Similarly, studies on carotid hemodynamics tion were higher in pre-hypertensive patients compared to and large artery stiffening on hypertensive patients report healthy volunteers, however among pre-hypertensive pa- significant correlation with high or low sensitivity CRP [50, tients the inflammation markers were higher in those with 52-55] and high hsCRP levels seem to increase the risk of microalbuminuria [32]. stroke in hypertensive patients [56, 57]. Moreover, serum levels of IL-6, soluble receptor of TNF- Furthermore, Weng et al. in a prospective study concern- # type 1 and soluble receptor of TNF-# type 2 were found ing hypertensive patients without diabetes and vascular or higher in patients with target organ damage than in hyperten- renal complications at baseline, showed after a mean follow- sive patients without organ damage. Increasing levels of up period of 32 ±10 months, that patients that developed these molecules were associated with a progressive increase diabetes had higher baseline log-hsCRP and log-hsCRP, age in the number of organs damaged, suggesting that extensive and baseline glucose level were found to be independent hypertensive disease with involvement of more target organs predictors for future development of diabetes. The authors might be associated with greater inflammatory and apoptotic suggested that there might be a link between inflammation activation in these patients [67]. Jastrzebski et al. also found and the pathogenesis of diabetes in hypertensive patients higher levels of TNF-# in hypertensive patients with target Inflammation Markers in Essential Hypertension Medicinal Chemistry, 2014, Vol. 10, No. 7 675 organ damage compared with controls and hypertensive pa- factors for atherosclerosis, including hypertension, is the tients without target organ damage or associated clinical stimulation of leukocyte chemotaxis and adhesion to endo- condition [54]. thelial cells [76]. Soluble forms of cell adhesion molecules Additionally, Mahmud et al. reported significant correla- can be detected in plasma and increased levels have been tions between IL-6 and TNF-! levels and markers of arterial found to be associated with endothelial cell activation and stiffness such as pulse wave velocity and augmentation index inflammation [77, 78]. in hypertensive patients, however, only hsCRP was an inde- Several studies have reported higher soluble levels of pendent predictor of pulse wave velocity and augmentation various adhesion molecules such as e- and p-selectin, ICAM- index in a multiple stepwise regression model [55]. 1 and VCAM-1 in patients with essential hypertension com- Likewise, in a study of Naya et al. on hypertensive pa- pared to normotensive controls [78-83]. First to provide evi- tients, elevated plasma IL-6 and TNF-! levels were inde- dence were Buemi et al. who demonstrated the relationship pendent predictors of coronary endothelial dysfunction, rec- between increased blood pressure and increased plasma lev- ommending that plasma IL-6 and TNF-! might be useful for els of adhesion molecules. In their study, hypertensive pa- identifying the high-risk subgroup of hypertensive patients tients had higher soluble levels of e-selectin, VCAM-1, and with coronary endothelial dysfunction [68]. ICAM-1 than normotensives and even a short-term increase in blood pressure, induced with cold pressor test, was ac- Serum levels of TNF-! and IL-6 were also increased in companied by a significant increase in soluble levels of those proportion to urinary albumin excretion rate and might play molecules not only in hypertensive but also in normotensive an important role in the pathogenesis and the development of subjects. Authors proposed that the rise in soluble levels of hypertensive renal damage as Yu et al. suggested in a study the adhesion molecules was the effect of pressure increase concerning hypertensive patients [67]. In contrast, in a study caused by the cold pressor test on the endothelium since no from Tsioufis et al. investigating whether urinary albumin significant alterations were detected in the expression of ad- excretion was associated with markers of low-grade inflam- hesion molecules studied on the surface of monocytes and mation in hypertensive subjects, hs-CRP and not IL-18, nor lymphocytes [78]. soluble CD40 ligand (sCD40L), was associated to albumin- to-creatinine ratio, implying activation of different inflam- Concurrently, DeSouza et al. in a study including older matory pathways in the progression of renal and cardiovas- patients with uncomplicated hypertension showed a positive cular atherosclerotic disease [41]. correlation of soluble ICAM-1 and both systolic and dia- stolic blood pressure, while soluble VCAM-1 was positively Larrouse et al. found no differences in serum CRP, IL-6 correlated with systolic blood pressure and age, implying a and adhesion molecules (soluble intercellular adhesion link between inflammation, endothelial dysfunction and hy- molecule type 1 - sICAM-1, soluble vascular cell adhesion molecule type 1 - sVCAM-1) between salt-sensitive and salt- pertension [84]. resistant hypertensive patients, nevertheless salt-sensitive Similarly, hypertensive patients, in a study by Parissis hypertensives showed age-adjusted increased levels of p- et al., also exhibit higher levels of various inflammatory me- selectin and MCP-1 [70]. diators such as soluble adhesion molecules (ICAM-1, Another cytokine that has been studied in patients with VCAM-1 and p-selectin), plasma concentrations of granulo- hypertension is osteopontin. Osteopontin exhibits pro- cyte-macrophage colony-stimulating factor, MCP-1, macro- inflammatory action and has recently emerged as a clinically phage inflammatory protein-1a, RANTES, as well as plasma important marker since its plasma levels are elevated in athe- endothelin-1compared to normotensive controls. Besidesthat, rosclerotic disease and has been shown to correlate with fu- in hypertensives plasma endothelin-1 levels correlated sig- ture cardiovascular events in patients with chronic stable nificantly with plasma levels of soluble ICAM-1 and MCP-1 angina [71, 72]. In hypertension, osteopontin levels but not suggesting that these findings might reflect the unfavorable IL-6, TNF-! and hsCRP levels, were higher in patients with effects of hypertension on endothelial function [80, 85]. primary aldosteronism compared to patients with essential Additionally, Glowinska et al. in a study concerning hypertension, implying a relationship between aldosterone children and adolescents with risk factors for atherosclerosis, and inflammation [73]. Furthermore, a recent study from such as obesity, diabetes and hypertension, revealed elevated Stepien et al. revealed elevated ostepontin levels in hyper- concentrations of sICAM-1, sVCAM-1, and e-selectin in tensive individuals in comparison to normotensives and sig- these subjects compared with healthy controls. Particularly, nificant correlations were observed between osteopontin the highest concentrations of these molecules appeared in levels and (CRP) and plasma glucose [74]. obese children with coexisting hypertension [81]. Further- more, Chao et al. reviewed the interactions between integrins ADHESION MOLECULES and growth factors receptors in response to the increased Cell adhesion molecules (CAMs) participate in several mechanical stress on blood vessels in hypertension. They pathological conditions such as cancer and inflammatory concluded that integrins signaling contributes to vascular diseases. Selectins, integrins, cadherins and immunoglobulin changes in at least two ways: either by regulating vasocon- gene superfamily of adhesion receptors play a fundamental striction and vasodialation in reaction to sensing the altered role in endothelial cells-leukocytes adherence and subse- mechanical environment in the vessel wall or by participat- quent migration of white blood cells into perivascular tissue, ing in vascular smooth muscle cell proliferation and vascular contributing in the initiation of atherosclerotic process [75]. remodeling in response to biochemical stimulators such an- It has been suggested that a common feature of all major risk giotensin II [86]. 676 Medicinal Chemistry, 2014, Vol. 10, No. 7 Tsounis et al.

Moreover, some studies investigated adhesion molecules Alpha 1-microglobulin is an immunomodulatory protein, as prognostic marker of hypertension, while others explored synthesized in liver and kidneys, that exists in blood as both their role as mediators of hypertensive vascular injury. For free/unbound and complexed with IgA and albumin forms. example, Xu et al. supported that the upregulation of junc- Urinary excretion of alpha 1-microglobulin is increased in tional adhesion molecule-A (JAM-A) might be triggered by renal tubular dysfunction, so it is considered an index of angiotensin II T1 receptor-mediated signaling preceding the early tubular damage [96, 97]. In newly diagnosed hyperten- stable elevation of blood pressure. These observations raise sive, non-diabetic patients with normal renal function Vys- an intriguing possibility of using JAM-A as an early soulis et al. observed that urinary excretion of alpha 1- biomarker of pre-hypertensive state [87]. Elsewhere, Cottone microglobulin was independently associated with acute et al. showed elevated soluble ICAM-1 and VCAM-1 levels phase proteins, which might reflect the overall patients’ in- in patients with essential hypertension without diabetes or flammatory status and that systolic hypertension was a major echocardiographic evidence of atherosclerosis compared to contributor to urinary excretion of alpha 1-microglobulin normal controls and also among hypertensive patients with [98]. microalbuminuria compared to those without microalbumin- uria, implying that in essential hypertension there is a very Finally, Gunes et al. showed that visfatin, a peptide se- early activation of the endothelial adhesion molecules that creted by visceral and stimulate pro-inflammatory cytokines, favors atherosclerosis [88]. was higher in hypertensive patients than healthy controls. Moreover, visfatin levels were proportional to the hyperten- OTHER INFLAMMATION MARKERS sion stage as well as higher in pre-hypertensive patients than in participants with normal blood pressure [99]. In a different A number of novel inflammatory markers have been manner, Dogru et al. evaluated visfatin levels and reported investigated in patients with essential hypertension, among no significant difference between young hypertensive pa- them soluble CD40 ligand (sCD40L), human cartilage tients and the control group. However, it is not clear whether glycoprotein 39 (YKL-40), Alpha 1-microglobulin and patients’ young age affects these findings [100]. visfatin. Soluble CD40 ligand (sCD40L) is involved in the patho- TREATMENT PERSPECTIVES genesis of cardiovascular risk factors associated with vascu- The involvement of inflammatory processes in the patho- lar damage and has been regarded as a molecular link be- genesis of hypertension as well as in the development of tween inflammation, thrombosis and angiogenesis [89]. target organ damage has intrigued the scientific interest on Studies have shown that angiotensin II promotes and aug- whether current hypertensive drugs have pro- or anti- ments the inflammatory activation induced by CD40/CD40L inflammatory effects and whether new drugs with proven ligation in human vascular cells and sCD40L levels have anti-inflammatory action have any effect on modifying been found elevated in hypertensive patients, which might be hemodynamics and outcomes on hypertensive patients. useful inidentifying hypertensive patients at a high risk of cardiovascular events [90, 91]. Indeed, Alioglu et al. showed Diuretics, for a long time, have remained the cornerstone that non-dippers had enhanced sCD40L levels that might of antihypertensive treatment and they were thought to have contribute to higher susceptibility for developing vascular anti-inflammatory effects, by enhancing natriuresis, since damage in this hypertensive group [92]. Yuan et al. also re- salt is shown to increase the isoprostane 8-iso-prostaglandin vealed a link between sCD40/CD40L levels and hyperten- F2!, therefore, oxidative stress in hypertensive humans sive target organ damage and that might be of predictive [101]. Nevertheless, hydrochlorothiazide treatment did not value. In their study sCD40 levels were closely associated to improve neutrophil superoxide anion, MCP-1, sVCAM-1, or the severity of hypertensive target organ damage. In contrast, low-density lipoprotein oxidation in hypertensive patients it is aforementioned that patients with essential hypertension after 4 weeks of treatment [102]. Additionally, Erikkson and microalbuminuria presented increased hsCRP, but not et al. suggested that the diabetogenic potential of thiazide IL-18 and sCD40L levels [41]. diuretics in obese-hypertensives are based on pro- inflammatory mechanisms. In this study after 12 weeks of YKL-40, a heparin and chitin binding glycoprotein, has hydrochlorothiazide therapy, the reductions in insulin sensi- been proposed as a new marker of inflammation, atheroscle- tivity and the ratio of subcutaneous to visceral fat, combined rosis and endothelial dysfunction in neoplastic, cardiovascu- with an increasein hepatic fat content and glycosylated he- lar and metabolic diseases [93]. In hypertensive patients, moglobin, were associated with stimulation of the inflamma- Diao et al. detected higher YKL-40 levels than normotensive tory marker, hsCRP [103]. controls and a positive correlation to blood pressure level but not to endothelin-1, NO and flow-mediated dilatation. Vasodilatory b-blockers, such as carvedilol and bi- Authors inferred that this novel biomarker might be used to soprolol are proven to have anti-apoptotic, antioxidant and reflect inflammation status but not endothelial function in anti-inflammatory effects, whereas, non-vasodilatory agents, hypertensive patients [95]. Ma et al. also showed signifi- such as atenolol and metoprolol, do not prevent up- cantly increased YKL-40 levels in essential hypertension regulation of inflammatory and pro-thrombotic molecules group and further increased in those with combined microal- and do not improve oxidative stress status in hypertensive buminuria compared with those without microalbuminuria. patients [104-109]. However, YKL-40 levels were independently associated Furthermore, vasodilatory calcium channel blockers also with parameters of arterial stiffness implying a mechanism exhibit pleiotropic effects that are related to anti- possibly related to arterial endothelium dysfunction [95]. inflammatory actions. Specifically, dihydropyridines in hy- Inflammation Markers in Essential Hypertension Medicinal Chemistry, 2014, Vol. 10, No. 7 677 pertensive patients inhibit cytokines (osteopontin, IL-1b, tive and vascular protective effect in hypertensive obese rats TGF-b1) synthesis and adhesion molecules (VCAM-1, [130-136]. ICAM-1) expression and diminish oxidative stress by reduc- ing superoxide, peroxynitrite and isoprostanes in endothelial, CONCLUSION vascular smooth muscle and circulating mononuclear cells [108, 110-114]. Inflammation has been recognized as an important pathophysiological factor in hypertension. Many inflamma- However, the most studied antihypertensive agents with tion markers such as CRP, cytokines, and adhesion mole- proven anti-inflammatory and antioxidant effect are blockers cules have been found elevated in hypertensive patients of renin-angiotensin-aldosterone system. Angiotensin con- compared to normotensives, further supporting the role of verting enzyme inhibitors (ACEi) decrease the expression of inflammation in hypertension. Moreover, they have been IL-6, sCD40L, adhesion molecules and selectins in patients associated with the risk of developing hypertension in nor- with hypertension, improve endothelial function and sup- motensive individuals, while in hypertensive patients there is press plasma aldosteronelevels [115-117]. Besides, mineral- a strong association with target organ damage and risk for ocorticosteroid receptor blockers (MRAs) such as spi- future cardiovascular events. Furthermore, anti-hypertensive ronolactone and eplerenone, exhibit various pleiotropic ef- agents apart from blood pressure lowering effect, also seem fects including anti-inflammatory action by inhibiting multi- to reduce inflammation markers whilst agents with proven ple cytokines, chemmoattractants, pro-inflammatory en- pleiotropic effects, including statins and PPARs, seem to zymes and growth factors along with markers of oxidative have favorable effects regarding inflammationin hyperten- stress [118-121]. sive patients, providing new insights for the treatment of In several clinical studies, angiotensin II receptor block- hypertension and its complications. ers (ARBs) have been shown to reduce inflammation mark- ers in hypertensive patients and their anti-infammatory ac- CONFLICT OF INTEREST tion seems to be superior to that of calcium channel blockers The authors confirm that this article content has no (CCB). Particularly, ARBs treatment in hypertensive patients conflict of interest. attenuated MCP-1 gene expression and reduced hs-CRP, TNF-!, IL-6, osteopontin, sCAM-1, sCD40L and pentraxin 3 ACKNOWLEDGEMENTS levels [102, 110, 122-125]. Beyond, the combination of the ARB-olmesartan with the CCB-amlodipine proved to be Declared none. more efficient than the combination with hydrochlorothiaz- ide, in improving metabolic status and reducing inflamma- REFERENCES tory markers in hypertensive patients with metabolic syn- [1] Mancia, G.; Fagard, R.; Narkiewicz, K.; Redon, J.; Zanchetti, A.; drome, while both combinations achieved adequate BP con- Böhm, M.; Christiaens, T.; Cifkova, R.; De Backer, G.; trol, exhibiting similar anti-hypertensive action [113]. Dominiczak, A.; Galderisi, M.; Grobbee, D. E.; Jaarsma, T.; Kirch- Regarding the pleiotropic effects of statins and mostly hof, P.; Kjeldsen, S. E.; Laurent, S.; Manolis, A. J.; Nilsson, P. M.; Ruilope, L. M.; Schmieder, R. E.; Sirnes, P. 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Received: December 08, 2013 Revised: December 30, 2013 Accepted: January 05, 2014