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Early Inflammatory Responses in Experimental Cardiac Hypertrophy and Fibrosis: Effects of 11ß-Hydroxysteroid Dehydrogenase Inactivation

Baker Medical Research Institute (M.J.Y., L.M., R.D., J.W.F.), Melbourne Prahran 3181, Australia; and Prince Henry’s Institute of Medical Research (M.J.Y., J.W.F.), Clayton, Victoria 3168, Australia

	Abstract

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In epithelial tissues such as kidney, mineralocorticoid receptors (MR) are protected against glucocorticoid occupancy by the enzyme 11ß-hydroxysteroid dehydrogenase (11ßHSD) type 2. If the enzyme is congenitally inactive, or blocked by carbenoxolone, physiologic glucocorticoids act as MR agonists in such tissues. In most nonepithelial tissues, including cardiomyocytes, 11ßHSD2 is expressed at minimal levels; in these tissues physiologic glucocorticoids act as MR antagonists, with the basis for this tissue selectivity currently unknown. Vascular smooth muscle cells (VSMC) express MR and 11ßHSD1/2, with 11ßHSD1 reported to show uncharacteristic oxidase activity, so that VSMC thus constitute a potential physiologic aldosterone target tissue. Because mineralocorticoid/salt administration triggers marked inflammatory responses in coronary vasculature, we reasoned that VSMC (like epithelial) MR may be activated by glucocorticoids if the protective enzyme is blocked. We thus gave uninephrectomized rats 0.9% NaCl solution to drink, and deoxycorticosterone (DOC, as a single 20 mg sc dose) or carbenoxolone (CBX, 2.5 mg/d in the drinking solution). Both DOC and CBX increased systolic blood pressure, heart, and kidney weight, and expression of cyclooxygenase 2, ED-1-positive macrophages, and osteopontin, with effects of both DOC and CBX blocked by the selective MR antagonist eplerenone. These findings suggest that local glucocorticoid excess, reflecting lower VSMC 11ßHSD1/2 activity may mimic systemic mineralocorticoid excess, and play a direct etiologic role in coronary vascular inflammatory responses under circumstances of a high salt intake.

	Introduction

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OVER THE PAST decade, a number of laboratories have shown that cardiac hypertrophy and fibrosis follow administration of exogenous mineralocorticoid to uninephrectomized rats maintained on 0.9% NaCl drinking solution (1, 2, 3, 4, 5, 6). In the initial studies (1, 2), rats were infused with aldosterone via osmotic minipumps for up to 8 wk, when both cardiac hypertrophy and marked perivascular and interstitial fibrosis were noted. Several lines of evidence suggest that this is a direct humoral rather than secondary hemodynamic effect. First, equivalent levels are seen in right and left ventricles despite the pressure differentials (1). Secondly, in rats infused peripherally with aldosterone but intracerebroventricularly (ICV) with RU28318, an MR antagonist, blood pressure is clamped at normal levels, but the cardiac effects are indistinguishable from those seen in aldosterone-infused rats receiving vehicle ICV (5). Finally, coadministered spironolactone (6) or potassium canrenoate (7) block the cardiac hypertrophy and fibrosis at doses, which do not substantially lower blood pressure.

Subsequent studies have addressed the time course of evolution of these cardiac responses. In the aldosterone/salt model, no increase in collagen deposition was noted over the first 3–4 wk of steroid administration (3, 8), although a more rapid time course has been reported after bolus doses of deoxycorticosterone (DOC; Ref. 9). In more recent studies, attention has focused on the coronary vasculature as a candidate early site for the cardiac response to mineralocorticoid/salt imbalance. In such studies, rats were maintained on 0.9% NaCl to drink and infused with angiotensin II (10) or aldosterone (11). Animals were killed after 1, 2, or 3 wk (angiotensin) or 1, 2, and 4 wk (aldosterone) of treatment, and tissue responses analyzed by morphometry, in situ hybridization and immunohistochemistry. After 1 wk of aldosterone/salt, for example, modest elevation of a variety of inflammatory markers (e.g. ED-1-positive macrophages; cyclooxygenase 2, COX-2; osteopontin) was seen. Some of these responses plateaued at 2 wk, with others still increasing at 4 wk. In all instances, the elevation in inflammatory markers, and the morphologic changes (vascular onion skinning, intense perivascular inflammatory cell infiltration) were reduced to near control levels by concomitant administration of eplerenone (EPL).

In contrast with cardiomyocytes, vascular smooth muscle cells (VSMC) express not only MR but also substantial levels of the enzymes 11ß-hydroxysteroid dehydrogenase (11ßHSD) types 1 and 2 (12). Unlike most tissues, 11ßHSD1 in VSMC appears to act both as a dehydrogenase and reductase, and enzyme blockade by carbenoxolone in VSMC has been shown to allow cortisol to occupy and activate MR (12). In 11ßHSD-protected MR, cortisol (or corticosterone) appears to act as MR agonists, mimicking the effects of aldosterone (13, 14). In contrast, in nonprotected cells such as cardiomyocytes (15) or A3V3 neurons (16), there is strong evidence that corticosterone does not mimic aldosterone, but rather acts as an MR antagonist.

In previous studies in which 30-fold higher corticosterone was coinfused with aldosterone to uninephrectomized rats on 0.9% NaCl for 8 wk, we have shown reduced levels of perivascular and interstitial cardiac fibrosis, consistent with a physiological antagonist effect of the glucocorticoid on cardiomyocyte MR (7). Given that in human VSMC cortisol has been shown to be MR agonist (12), we reasoned that glucocorticoid excess may tend to mimic the vascular effects of aldosterone/salt in terms of the inflammatory response, while at the same time acting to mollify the action of aldosterone/salt on the cardiomyocyte. To test this hypothesis, we have compared the effects of administered DOC with those of the 11ßHSD1/2 inhibitor carbenoxolone, to allow endogenous corticosterone to access coronary VSMC MR, on the early cardiac response to MR activation.

	Materials and Methods

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Protocols for animal use in this study were approved by the Animal Ethics Committee of the Baker Medical Research Institute. Male Sprague Dawley rats (190–210 g starting weight) were uninephrectomized under anesthesia with ilium xylazil (8 mg/kg; Troy Laboratories, Smithfield, New South Wales, Australia) and ketamine (60 mg/kg: Park-Davis, Auckland, New Zealand) with carprofen (5 mg/kg: Pfizer, Inc., New York, NY) for postoperative analgesia. Rats were then maintained on chow ad lib and 0.9% NaCl solution to drink, and allocated into six treatment groups as follows: 1) control, receiving vehicle (ethanol, corn oil) sc on study d 2 (CON, n = 9); 2) DOC (n = 7; Sigma, St. Louis, MO; 20 mg in corn oil sc on study d 2); 3) EPL (n = 8; Pharmacia, Skokie, IL; incorporated into the chow by Glenforest Stock Feeders, Perth, Australia, at a level to provide approximately 100 mg/kg·d); 4) carbenoxolone (CBX, n = 8; Sigma; administered in the drinking solution to provide approximately 2.5 mg/d); 5) DOC plus EPL (n = 7); and 6) carbenoxolone plus EPL (n = 8), at the doses quoted above. For groups 4 and 6, the concentration of carbenoxolone in the drinking fluid was adjusted daily on the basis of body weight and volume consumed.

Rats were acclimated to the blood pressure measuring device for 1–2 wk before surgery, with measurements made every 3 d over the course of the study. Animals were killed on study d 10, and an arterial blood sample taken, centrifuged and the plasma frozen, kidneys and hearts were excised, weighed, fixed in buffered paraformaldehyde for 12–16 h, and then rinsed and stored overnight in PBS before paraffin embedding.

Histologic analysis
Tissue blocks were sectioned in the mid-coronal plane at 5-µm thickness onto glass slides, and myocardial collagen levels determined by picrosirius red staining. Immunochemistry for inflammatory cytokines used antibodies sourced from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA) for COX-2, the University of Iowa Hybridoma Bank (Iowa City, IA) for osteopontin, and Dr. P. Tipping (Monash University, Clayton, Australia) for ED-1. Sections were dewaxed by two 5-min washes in xylene, and rehydrated through graded alcohol by 3-min washes with a final wash in water. They were then blocked in 0.3% H₂O₂ in Tris-buffered saline (TBS), and washed three times for 5 min in TBS. For osteopontin and ED-1, a standard citrate boiling antigen retrieval procedure was used, but for COX-2 no retrieval was necessary. Sections were then washed three times for 5 min in TBS, the primary antibody added (COX-2, 1:100; osteopontin, 1:10; ED-1, 1:400), and the sections incubated overnight at 4 C. The following day, they were rinsed (three times for 5 min in TBS) and the appropriate secondary antibody added at a dilution 1:200 in TBS added for 1 h, followed by three 5-min washes in TBS. Preincubated ABC complex and filtered diaminobenzidine were applied and nuclei counterstained with hematoxylin before mounting in Depex (BDH Merck, Poole, UK). Collagen content and level of inflammatory marker expression are expressed as percentage of area per field analyzed; for each marker, 10–12 fields were analyzed in each individual rat. Small and medium-sized coronary arteries were scored on a scale of 0–3 for marker expression in vessel wall (see Fig. 1). Statistical comparison was by one-way ANOVA, with two sets of groups compared: 1) control, DOC, EPL and DOC plus EPL; and 2) control, DOC, carbenoxolone and carbenoxolone plus EPL. For determination of collagen content and for scoring of immunohistochemical staining, 10–12 fields were analyzed for each section. These values were averaged so that one value per animal was used in the one-way ANOVA test.

View larger version (90K): [in this window] [in a new window]   Figure 1. Representative photographs of immunohistochemical staining for ED-1 (A–D), osteopontin (E–H), and COX-2 (I–L). Magnification, x10.

	Results

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View larger version (12K): [in this window] [in a new window]   Figure 2. DOC acetate (DOC; 20 mg sc on d 2) compared with control (CON; vehicle only), the MR antagonist EPL (100 mg/kg·d orally) and DOC plus EPL. A, Change in systolic blood pressure over the 8 d of treatment. DOC increased systolic blood pressure (P < 0.05) during the study and that this was not blocked by EPL. B and C, Indices of, respectively, cardiac and renal hypertrophy are shown. Slight increases were detected in DOC-treated rats, and this was blocked by EPL (P < 0.05). D–F, Scores for inflammatory marker expression, ED-1, osteopontin, and COX-2, respectively, indicated that DOC markedly increased each parameter above control (P < 0.05) and that this was blocked by cotreatment with EPL. G, Percent area collagen in the heart; at this early time point (8 d after treatment), there were not significant differences between the treatment groups. n = 8 for all groups except for CON (n = 9) and DOC and DOC plus EPL (n = 7).

Figure 3 recapitulates the previously shown control and DOC values, as baseline and positive control values for comparison with the effects of carbenoxolone. Carbenoxolone alone raises blood pressure to levels similar to those seen with DOC, an effect that is not blocked by EPL (panel A). Carbenoxolone similarly increases organ weight (panels B and C) and marker expression (panels D–F) to levels clearly above control and comparable with those seen in DOC-treated animals In contrast with its lack of effect on blood pressure, EPL blocks the carbenoxolone-induced increases in organ weight and inflammatory marker expression (panels B–F). Again, at this relatively early stage in the response, no effect of carbenoxolone on cardiac fibrosis is seen (panel G).

View larger version (11K): [in this window] [in a new window]   Figure 3. DOC (20 mg sc on d 2) compared with CON, CBX (2.5 mg/d), and CBX plus CON. A, Change in systolic blood pressure over the 8 d of treatment. CBX increased systolic blood pressure (P < 0.05) during the study to the same extent as DOC, and that this was not blocked by EPL. B and C, Indices of, respectively, cardiac and renal hypertrophy are shown. Slight increases and were detected in CBX as in DOC-treated rats, and this was blocked by EPL (P < 0.05). D–F, Scores for inflammatory marker expression, ED-1, osteopontin, and COX-2, respectively, indicated that CBX and DOC markedly increased each parameter above control (P < 0.05) and that this was blocked by cotreatment with EPL. G, Percent area collagen in the heart; at this early time point (8 d after treatment), there were not significant differences between the treatment groups. n = 8 for all groups except for CON (n = 9).

	Discussion

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Rocha et al. (19) have shown EPL to be a potent blocker of the cardiac and renal damage seen in a number of rat models: aldosterone/salt, L-NAME plus angiotensin II (10), angiotensin II/salt (11), and the stroke-prone spontaneously hypertensive rat (20). In most of these experimental models, the doses of EPL used were without effect on blood pressure elevation, as was the case in the present study, and in previous studies using spironolactone (6) or potassium canrenoate (5). Our interpretation of these findings, taken together, is that although EPL clearly has antihypertensive activity in a variety of clinical and experimental situations, it is relatively more potent in blocking vascular end organ pathology, as is also the case for the relatively nonselective MR antagonists spironolactone and potassium canrenoate.

In terms of time course, the present studies mirror the aldosterone/salt experiments reported by Rocha et al. (19) more clearly than our previous DOC/salt studies (9), for reasons that are not clear. In the previous studies, in addition to marked vascular and perivascular infiltration of inflammatory cells, much higher elevation of blood pressure and evidence for collagen deposition, at both the mRNA and protein levels, was seen at 8 d. Although the study design was not identical, in that the previous animals received weekly injections of DOC rather than a single dose 8 d before, it is improbable that this difference can explain the much more marked responses observed. The present study, perhaps fortuitously, is such that the hypertrophic and inflammatory effects of coronary and cardiac MR activation clearly precede any significant collagen deposition, despite the observations being made at a single 8-d time point.

Perhaps the most biologically significant finding of the present studies is that in the presence of excess salt endogenous glucocorticoids, acting via MR, can produce the same spectrum of coronary vascular inflammatory response as elevated levels of mineralocorticoid hormones, providing that they can access the MR in VSMC. Alzamora et al. (12) have shown that the rapid nongenomic effect of aldosterone on Na⁺/H⁺ exchange can be blocked by the MR antagonist RU28318, and mimicked in the presence of carbenoxolone by cortisol; in the absence of carbenoxolone, i.e. when 11ßHSD is operant, cortisol is without effect. These studies clearly suggest that these rapid nongenomic effects of aldosterone are not only MR mediated, but are mediated via normally protected and thus glucocorticoid-inaccessible MR. The present studies extend those observations to the in vivo situation and provide further evidence that the VSMC, with its 11ßHSD protected MR, may be a physiologic aldosterone target tissue. Both carbenoxolone and EPL have actions on the kidney (and other epithelial tissues) as well as in VSMC. We believe, for example, that the effects seen on blood pressure and heart and kidney weight, may primarily reflect epithelial actions of both agents. On the other hand, the effects observed on VSMC, and the lack of effects on fibrosis, underscore the difference between cardiomyocyte (MR positive and 11ßHSD negative) and the VSMC (MR positive and 11ßHSD positive).

If this is the case, that VSMC like the kidney are physiologic aldosterone target tissues, then the present findings may have implications beyond the experimental use of carbenoxolone in animals on a high salt intake. Among the possible clinical implications is 1) that normal circulating levels of glucocorticoids may not only cause abnormal sodium retention and hypertension, as in the syndrome of apparent mineralocorticoid excess, but may also have direct vasculopathic effects if they can access VSMC MR; 2) that local alterations in 11ßHSD activity, or in the ratio of its cosubstrate NAD/NADH, to allow inappropriate access of glucocorticoids to VSMC MR, may produce outcomes similar to those demonstrated experimentally in the present study; and 3) that VSMC may thus be particularly susceptible to MR activation, compared with cells in which glucocorticoids appear to act as constitutive MR antagonists. This may underlie what appears to be the most salient aspect of MR activation/salt imbalance, that of the independent end organ effects reflecting damage to blood vessels in the brain, kidney and heart.

	Footnotes

 
Address all correspondence and requests for reprints to: Professor John W. Funder, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: John.Funder{at}med monash.edu.au.

Abbreviations: CBX, Carbenoxolone; COX, cyclooxygenase; DOC, deoxycorticosterone; EPL, eplerenone; 11ßHSD, 11ß-hydroxysteroid dehydrogenase; ICV, intracerebroventricular(ly); MR, mineralocorticoid receptor; TBS, Tris-buffered saline; VSMC, vascular smooth muscle cells.

Received September 23, 2002.

Accepted for publication December 4, 2002.

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