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Am J Physiol Heart Circ Physiol 288: H111-H115, 2005. First published August 12, 2004; doi:10.1152/ajpheart.01061.2003
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Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-{kappa}B/I{kappa}B system

David Sanz-Rosa,1 M. Pilar Oubiña,1 Eva Cediel,1 Natalia de las Heras,1 Onofre Vegazo,2 Javier Jiménez,2 Vicente Lahera,1 and Victoria Cachofeiro1

2Medical Department, AstraZeneca Farmacéutica Spain, and 1Department of Physiology, School of Medicine, Universidad Complutense, Madrid, Spain

Submitted 10 November 2003 ; accepted in final form 4 August 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We investigated the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR). IL-1{beta}, IL-6, and TNF-{alpha} aortic mRNA expression and plasma levels were measured in adult SHR untreated or treated with the angiotensin II receptor antagonist candesartan (2 mg·kg–1·day–1) or antihypertensive triple therapy (TT; in mg·kg–1·day–1: 20 hydralazine + 7 type 1 hydrochlorothiazide + 0.15 reserpine) for 10 wk. Likewise, aortic expression of NF-{kappa}B p50 subunit precursor p105 and its inhibitor (I{kappa}B) were measured. Age-matched Wistar-Kyoto rats (WKY) served as normotensive reference. High blood pressure levels were associated with increased (P < 0.05) aortic mRNA expression of IL-1{beta}, IL-6, and TNF-{alpha}. Hypertension was also accompanied by increased IL-1{beta} and IL-6 plasma levels. No differences were observed in circulating TNF-{alpha} levels between SHR and WKY. SHR presented elevated aortic mRNA expression of the transcription factor NF-{kappa}B and reduction in its inhibitor, I{kappa}B. Candesartan decreased (P < 0.05) blood pressure levels, aortic mRNA expression of IL-1{beta}, IL-6, and TNF-{alpha}, and (P < 0.05) IL-1{beta} and IL-6 plasma concentration. However, although arterial pressure decrease was comparable for the treatments, TT only partially reduced the increments in inflammatory markers. In fact, candesartan-treated rats showed significantly lower levels of circulating and vascular inflammatory markers than TT-treated animals. The treatments increased I{kappa}B mRNA expression similarly. However, only candesartan reduced NF-{kappa}B mRNA expression. In summary, 1) SHR presented a vascular inflammatory process; 2) angiotensin II, and increased hemodynamic forces associated with hypertension, seems to be involved in stimulation of inflammatory mediators through NF-{kappa}B system activation; and 3) reduction of inflammatory mediators produced by candesartan in SHR could be partially due to both downregulation of NF-{kappa}B and upregulation of I{kappa}B.

angiotensin II; cytokines

HYPERTENSION IS a primary risk factor for atherosclerosis. The intrinsic mechanisms by which elevated arterial pressure levels lead to atherosclerosis are not totally established, although mechanical stress and subsequent endothelial dysfunction have been implicated (15, 25, 33). Endothelial dysfunction has been characterized mainly by impaired endothelium-dependent relaxation (27, 30, 35). Reduced availability of nitric oxide due to a diminution of its synthesis and/or enhanced degradation by superoxide anions has been implicated as a major cause of endothelial dysfunction in hypertension (5, 17, 30, 37). In addition, an increase in the production of cytokines and other mediators of inflammation has been associated with endothelial dysfunction (11, 20). Inflammation plays a key role in the development of atherosclerosis, which is considered a chronic inflammatory disease (3). However, the relationship between inflammation and hypertension is not well established because the effect of high blood pressure on inflammatory markers is not well determined. This is due to the variety of markers measured in different studies, the origin (local or circulating) of the markers, as well as the contradictory results reported in different studies (2, 16, 21, 23, 26, 32). In addition, the concomitant presence of other cardiovascular risk factors such as obesity, age, and diabetes could have increased inflammation and in turn been responsible for this variety of results (9, 21).

Angiotensin II, the main active component of the renin-angiotensin system, plays an important role in the functional and vascular alterations associated with hypertension. Furthermore, administration of either angiotensin-converting enzyme inhibitors or angiotensin II type 1 (AT1) receptor antagonists is able to improve endothelial dysfunction and vascular remodeling in clinical and experimental hypertension (7, 14, 27, 28, 30). In addition, angiotensin II is considered a proinflammatory mediator that plays a pivotal role in the inflammatory process underlying development and complications of atherosclerosis (4, 24). This role involves activation of transcription factors such as NF-{kappa}B, which participates in the regulation of numerous inflammatory factors including cytokines, chemokines, and adhesion molecules (4, 19, 29). However, whether angiotensin II is involved in the inflammatory response associated with hypertension is not well established. Therefore, the aim of this study was to investigate 1) the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR) and 2) the possible involvement of the NF-{kappa}B/I{kappa}B system in the effect of angiotensin II on inflammatory mediators in SHR. To this end, we studied aortic mRNA expression and plasma levels of IL-1{beta}, IL-6, and TNF-{alpha} in SHR untreated or treated with the AT1 receptor antagonist candesartan. In addition, we evaluated the mRNA expression of the NF-{kappa}B p50 subunit precursor p105 (31) and of its inhibitor (I{kappa}B) in aortas from the same rats. To elucidate whether the changes produced by candesartan could be due to blood pressure reduction or AT1 receptor blockade, we examined the same parameters in SHR treated with the antihypertensive triple therapy (TT) of hydralazine + hydrochlorothiazide + reserpine. A group of Wistar-Kyoto rats (WKY) were used as normotensive reference.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Studies were performed in male SHR (20–22 wk old; n = 24) from Harlam Interfauna Ibérica (Barcelona, Spain). Animals were fed a standard chow (A=04; Panlab, Barcelona, Spain) and had free access to drinking water. Animals were treated with vehicle, candesartan (2 mg·kg–1·day–1; AstraZeneca, Goteborg, Sweden), or TT (in mg·kg–1·day–1: 20 hydralazine + 7 hydrochlorothiazide + 0.15 reserpine) given in the drinking water for 10 wk. The doses of candesartan and TT were chosen from previously published studies and adjusted to induce a comparable decrease in blood pressure (24, 36). WKY (n = 8) of the same age were used as a normotensive reference group. At the end of the treatment, systolic arterial pressure was measured by a tail-cuff plethysmograph (Narco Bio-Systems, Houston, TX) as previously described (28). On the day of the experiment, animals were killed by decapitation, and blood was collected in prechilled glass tubes containing EDTA. The aorta was isolated for molecular biology determinations. Isolation and manipulation of the aorta were always performed under sterile conditions. All experimental procedures were approved by the Animal Care and Use Committee of Universidad Complutense, according to the guidelines for ethical care of experimental animals of the European Union.

Plasma cytokine levels. Plasma IL-1{beta}, IL-6, and TNF-{alpha} were measured with a quantitative sandwich enzyme immunoassay. A rat-specific monoclonal antibody for IL-1{beta}, IL-6, or TNF-{alpha} was precoated onto microplates (R&D Systems, Minneapolis, MN). The minimum detectable dose was 5 pg/ml for IL-1{beta} and TNF-{alpha} and 10 pg/ml for IL-6, with standard curve ranges of 3.9–2,000 pg/ml and 12.5–800 pg/ml for IL-1{beta} and IL-6 and for TNF-{alpha}, respectively.

RNA isolation. Frozen rat aortas were pulverized in liquid nitrogen and homogenized together with 1 ml of Tri Reagent. RNA isolation was performed according to the Chomczynski method (10). RNA was quantified by optical density measurement at 260 nm with a BioPhotometer (Eppendorf). RNAs were frozen at –20°C until used.

Reverse transcription for cDNA synthesis. Five micrograms of total RNA were taken to perform reverse transcription. It was previously heated with 2 µM random hexamer at 70°C for 5 min and quickly chilled on ice. Subsequently, a mixture of 0.7 U RNase inhibitor, 25 mM Tris·HCl (pH 8.3), 37 mM KCl, 1.5 mM MgCl2, 10 mM DTT, each dNTP at 0.4 mM, and 2.5 U of Moloney murine leukemia virus reverse transcriptase was added and incubated at 37°C for 60 min, followed by heating at 95°C for 10 min and chilling on ice. The mixture was then completed with DNase-free water for a final volume of 50 µl.

Multiplex polymerase chain reaction. Five microliters of the above-mentioned cDNA were taken for a multiplex polymerase chain reaction (MPCR) reaction (MPCR kit for Rat Inflammatory Genes Set-2; Maxim Biotech, San Francisco, CA). A mixture of MPCR buffer, Taq DNA polymerase (2.5 U), and specific MPCR primers for IL-6, IL-1{beta}, TNF-{alpha}, NF-{kappa}B p50 subunit, I{kappa}B, and GADPH was added. The following time-temperature profile was used to perform MPCR: 2 cycles of 1 min at 96°C and 2 min at 58–60°C; 27 cycles for amplification of IL-1{beta}, p105, I{kappa}B, and GAPDH genes and 32 cycles for IL-6 and TNF-{alpha} of 1 min at 94°C and 2 min at 58–60°C; and 1 cycle of 10 min at 70°C and a final step of 25°C.

MPCR DNA product was fractioned electrophoretically on a 2% agarose gel containing 0.5 mg/ml ethidium bromide. The amplicon size of the genes was 532 bp for GAPDH, 453 bp for IL-6, 396 bp for p105, 351 bp for TNF-{alpha}, 294 bp for IL-1{beta}, and 167 bp for I{kappa}B. Band intensity was measured with Gel Analysis Software (Syngene, Cambridge, UK). Data were normalized with GAPDH intensity data.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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As shown in Table 1, SHR presented higher systolic arterial pressure levels than WKY (P < 0.05). Treatment with candesartan or TT markedly reduced systolic arterial pressure to levels that were not different between the treatments. All groups presented similar body weight at the end of the experiment (Table 1).


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  		Table 1. SAP levels and BW in WKY and SHR

 
Plasma levels of IL-6 and IL-1{beta} were higher (P < 0.05) in SHR compared with control animals (Fig. 1). Both candesartan and TT reduced plasma levels of IL-1{beta} and IL-6 in SHR, this effect being more marked with candesartan than with TT. In fact, plasma levels of both cytokines were significantly lower in candesartan-treated rats compared with rats receiving TT. Neither hypertension nor treatments modified plasma levels of TNF-{alpha}.



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  		Fig. 1. Plasma concentrations of IL-1{beta} (top) and IL-6 (bottom) in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) treated with vehicle (SHR), candesartan (C; 2 mg·kg–1·day–1), or triple therapy (TT; in mg·kg–1·day–1: 20 hydralazine + 7 hydrochlorothiazide + 0.15 reserpine) for 10 wk. Values are means ± SE for 8 rats. *P < 0.05 compared with WKY; #P < 0.05 compared with SHR treated with vehicle; {dagger}P < 0.05 compared with SHR treated with candesartan.

 
mRNA expression of IL-6, IL-1{beta}, and TNF-{alpha} in aorta homogenates was higher in SHR compared with WKY (Fig. 2). Both candesartan treatment and TT reduced the increase in mRNA expression of the three cytokines in hypertensive animals (Fig. 2), this reduction being more marked in the case of candesartan. Indeed, mRNA expression of the three cytokines was significantly lower in candesartan-treated animals than in TT-treated animals.



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  		Fig. 2. mRNA expression of IL-1{beta} (top), IL-6 (middle), and TNF-{alpha} (bottom) by multiplex polymerase chain reaction (MPCR) in aortas from WKY and SHR treated with vehicle, candesartan (2 mg·kg–1·day–1), or TT (in mg·kg–1·day–1: 20 hydralazine + 7 hydrochlorothiazide + 0.15 reserpine) for 10 wk. Representative MPCR of mRNA of IL-1{beta}, IL-6, and TNF-{alpha} are shown. Graphs show densitometric analysis of mRNA expression of IL-1{beta}, IL-6, and TNF-{alpha} expressed relative to WKY. Each bar represents mean ± SE of 6 animals. *P < 0.05 compared with WKY; #P < 0.05 compared with SHR treated with vehicle; {dagger}P < 0.05 compared with SHR treated with candesartan.

 
Hypertension also increased the aortic mRNA expression of p105, the NF-{kappa}B p50 subunit precursor, because levels were higher in SHR than WKY (Fig. 3). Candesartan, but not TT, was able to reduce this (Fig. 3). In contrast, expression of the NF-{kappa}B inhibitor I{kappa}B was reduced in aortas from SHR compared with WKY. Candesartan increased I{kappa}B expression to the same extent as TT treatment.



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  		Fig. 3. mRNA expression of the NF-{kappa}B p50 subunit precursor p105 (top) and the NF-{kappa}B inhibitor I{kappa}B (bottom) by MPCR in aortas from WKY and SHR treated with vehicle, candesartan (2 mg·kg–1·day–1), or TT (in mg·kg–1·day–1: 20 hydralazine + 7 hydrochlorothiazide + 0.15 reserpine) for 10 wk. Representative MPCR of mRNA of p105 and I{kappa}B are shown. Graphs show densitometric analysis of mRNA expression of p105 and I{kappa}B expressed relative to WKY. Each bar represents mean ± SE of 6 animals. *P < 0.05 compared with WKY; #P < 0.05 compared with SHR treated with vehicle; {dagger}P < 0.05 compared with SHR treated with candesartan.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present data show that SHR presented an elevated aortic expression of cytokines (IL-6, IL-1{beta}, and TNF-{alpha}) compared with WKY, suggesting an inflammatory process in the vascular wall associated with hypertension. This elevated vascular cytokine expression was accompanied by increased plasma levels of both IL-6 and IL-1{beta}. The inflammatory process appears to be mediated by angiotensin II as well as an increase in hemodynamic forces associated with hypertension through the upregulation of NF-{kappa}B as well as a downregulation of its inhibitor, I{kappa}-B.

The present study demonstrated that high arterial pressure is associated with an inflammatory process in the vascular wall because aorta from SHR showed an increase in the mRNA expression of IL-6, IL-1{beta}, and TNF-{alpha}. Similarly, an increase in other markers of inflammation, including ICAM, VCAM, monocyte chemoattractant protein (MCP-1), and IL-6 have been reported in vessels of hypertensive rats (16, 18, 21, 34). This inflammatory process can play a key role in the progression of vascular damage associated with hypertension and could lead to the development of atherosclerosis, which is considered a chronic inflammatory disease (3). In addition, the elevated vascular expression of cytokines was accompanied by high circulating concentrations of IL-6 and IL-1{beta}. Therefore, these data could suggest that hypertension is associated with a generalized inflammatory process because circulating levels may be generated from a variety of sources, including not only the vascular wall but also extravascular sources such as adipose tissue and blood cells (1, 6).

Mechanisms underlying the stimulation of both vascular and circulating inflammatory markers are not well established, although the participation of mechanical stress associated with hypertension can be suggested. This affirmation is based on the fact that reduction in either plasma concentrations or mRNA expression of inflammatory markers induced by both candesartan and TT was accompanied by a decrease in blood pressure. Therefore, these data support the notion that the stimulation of mechanoreceptors by elevated arterial pressure is involved in the inflammatory process observed in SHR. However, although the treatments produced a similar decrease in blood pressure, the effect on inflammatory markers was greater in candesartan-treated rats than in animals receiving an antihypertensive TT therapy that does not directly interact with AT1 receptors (36). Consequently, mechanical stress reduction seems not to be the only mechanism accounting for improvement in the inflammatory process induced by candesartan. The participation of angiotensin II through AT1 receptors in the inflammatory process associated with hypertension can, therefore, be proposed. Supporting this concept is the observation made by Tummala et al. (34) showing that the infusion of angiotensin II, but not of norepinephrine, for 6 days in rats induced an increase in VCAM-1 mRNA expression, although animals from both groups presented similar high blood pressure levels. Likewise, it has been shown that the administration of an AT1 receptor antagonist, but not a diuretic, decreased VCAM-1 and MCP-1 in hypertensive patients (26). Similarly, inhibition of angiotensin-converting enzyme or AT1 receptor antagonism reduces the inflammatory phenotype in the vessel wall in nitro-L-arginine methyl ester (L-NAME)-hypertensive rats (16, 21). In consequence, both the blockade of AT1 receptors as well as a mechanical stress reduction seem to be mechanisms accounting for improvement in the inflammatory process induced by candesartan.

Numerous studies have shown that NF-{kappa}B participates in the vascular, renal, and cardiac inflammatory processes observed in several nongenetic models of hypertension through its ability to activate a variety of inflammation-mediating genes (16, 19, 22, 34). The present data show that the increase in inflammatory mediators observed in SHR was associated with higher aortic mRNA expression of NF-{kappa}B than in normotensive rats and lower expression of I{kappa}B, which inhibits the translocation of NF-{kappa}B to the nucleus and consequently its activation. Therefore, the results suggest that a higher activation of the NF-{kappa}B system is involved in the stimulation of inflammatory markers observed in SHR. This concept is further supported by the fact that the inflammatory marker decrease induced by both treatments was accompanied by an increase in the expression of the inhibitor I{kappa}B. Furthermore, the changes in I{kappa}B expression observed in SHR seem to be mainly due to an increase in mechanical stress because the treatments not only prevent the changes to a similar extent but also reduce blood pressure in a comparable manner. In addition, the role of angiotensin II is also apparent in the changes in NF-{kappa}B system observed in SHR. This participation is supported by the fact that candesartan, but not TT, partially prevented the upregulation of NF-{kappa}B although both similarly reduced blood pressure. Moreover, this effect was accompanied with a larger reduction in inflammatory markers in the candesartan-treated than the TT-treated group. Similarly, NF-{kappa}B has been involved in the proinflammatory action of angiotensin II in other models of hypertension in rats. In this regard, it has been reported that an angiotensin-converting enzyme inhibitor reduced the expression of several inflammatory mediators in the aorta of L-NAME-hypertensive rats. This reduction was accompanied by a minor activity of NF-{kappa}B (17). Likewise, the inhibition of NF-{kappa}B is able to ameliorate the renal and vascular inflammatory process in rats with angiotensin II-induced hypertension (22).

In summary, the present results show that in rats, hypertension is associated with an inflammatory vascular process that can be one of the mechanisms by which elevated blood pressure levels lead to atherosclerosis. Angiotensin II, in addition to hemodynamic changes induced by hypertension, could be involved in the stimulation of these inflammatory mediators through an upregulation of NF-{kappa}B as well as a downregulation of its inhibitor, I{kappa}B. The reduction in inflammatory mediators produced by AT1 receptor blockade seems to partially involve the prevention of these changes in the mRNA expression of the NF-{kappa}B/I{kappa}B system.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología (SAF 2001-1864) and from Fondo de Investigaciones Sanitarias (FIS 01/0088-02). N. de las Heras was paid with a grant from Red Cardiovascular del FIS (C03/01).


   ACKNOWLEDGMENTS
 
We thank Blanca Martínez and Antonio Carmona for technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: V. Cachofeiro, Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain (E-mail: vcara{at}med.ucm.es)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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