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(Hypertension. 2003;42:737.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Peroxisome Proliferator-Activated Receptor- and Receptor- Activators Prevent Cardiac Fibrosis in Mineralocorticoid-Dependent Hypertension

Marc Iglarz; Rhian M. Touyz; Emilie C. Viel; Pierre Paradis; Farhad Amiri; Quy N. Diep; Ernesto L. Schiffrin

From CIHR Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.

Correspondence to Ernesto L. Schiffrin, MD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}ircm.qc.ca

	Abstract

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Peroxisome proliferator-activated receptor (PPAR) activation may prevent cardiac hypertrophy and inhibit production of endothelin-1 (ET-1), a hypertrophic agent. The aim of this in vivo study was to investigate the effects of PPAR activators on cardiac remodeling in DOCA-salt rats, a model overexpressing ET-1. Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were randomly divided into 4 groups: control rats, DOCA-salt, DOCA-salt+rosiglitazone (PPAR- activator, 5 mg/kg per day), and DOCA-salt+fenofibrate (PPAR- activator, 100 mg/kg per day). After 3 weeks of treatment, mean arterial blood pressure was significantly increased in DOCA-salt by 36 mm Hg. Mean arterial blood pressure was normalized by coadministration of rosiglitazone but not by fenofibrate. Both PPAR activators prevented cardiac fibrosis and abrogated the increase in prepro–ET-1 mRNA content in the left ventricle of DOCA-salt rats. Coadministration of rosiglitazone or fenofibrate failed to prevent thickening of left ventricle (LV) walls as measured by echocardiography and the increase in atrial natriuretic peptide mRNA levels. However, rosiglitazone and fenofibrate prevented the decrease in LV internal diameter and thus concentric remodeling of the LV found in DOCA-salt rats. Taken together, these data indicate a modulatory role of PPAR activators on cardiac remodeling in mineralocorticoid-induced hypertension, in part associated with decreased ET-1 production.

Key Words: endothelin • remodeling • fibrosis • hypertension, mineralocorticoid • collagen • hypertrophy

	Introduction

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Cardiac remodeling can occur as an adaptive process in response to increased peripheral resistance and elevated blood pressure. This process, associated with increased cardiomyocyte size and collagen deposition, is a deleterious outcome in hypertension, since it can lead to heart failure.¹ The DOCA-salt rat is a model of severe hypertension and is characterized by increased tissue endothelin-1 (ET-1) content and cardiac hypertrophy and fibrosis.^2,3 ET-1 has been described to induce cardiomyocyte growth in vitro^4,5 and to promote collagen synthesis by cardiac fibroblasts.⁶ We recently showed that increase of extracellular components (eg, procollagen I and III, fibronectin) in myocardium of DOCA-salt rats can be prevented by ET-type A receptor antagonists.^3,7 Moreover, some in vivo studies suggest a potential role for ET-1 in the development of left ventricular (LV) hypertrophy.⁸

Peroxisome proliferator-activated receptors PPAR are transcription factors present in numerous tissues (the -isoform highly abundant in adipose tissue and the -isoform in tissues with high rates of mitochondrial fatty acid ß-oxidation). Neonatal and adult rat cardiomyocytes also express PPAR- and to a much lower extent PPAR- isoform.⁹ Recent data indicate that PPARs play a critical role in the pathophysiology of cardiac hypertrophy. For instance, heterozygous PPAR-^+/- mice develop more accentuated LV hypertrophy than wild-type counterparts after aortic banding.¹⁰ Moreover, PPAR- activators have anti-inflammatory properties and inhibit cell migration and fibrosis.^11–13 LV hypertrophy is also associated with a shift of cardiac metabolism, in favor of glycolysis instead of fatty acid oxidation. It is well established that the main genes involved in fatty acid oxidation are regulated by PPAR- activity.¹⁴ Moreover, PPAR- expression is downregulated during pressure overload–induced cardiac hypertrophy.¹⁵

Recent studies indicate that PPAR- and PPAR- activators prevent vascular damage induced by hormonal factors such as angiotensin II.^16,17 Interestingly, PPAR- and PPAR- activation also inhibit production of ET-1 by endothelial cells through a direct interaction with AP-1.¹⁸

We proposed that PPAR activators such as fenofibrate () and rosiglitazone () may also affect cardiac remodeling through the modulation of hormonal factors such as ET-1. In this study, we investigated the impact of these agents on cardiac function and remodeling in DOCA-salt rats, a model of endothelin-dependent hypertension.

	Methods

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Animals
The study was conducted according to recommendations from the Animal Care Committee of the Clinical Research Institute of Montreal and the Canadian Council of Animal Care. DOCA-salt hypertension was induced in Sprague-Dawley rats weighing 225 g by the method of Ormsbee and Ryan.¹⁹ Six groups of rats (n=6 to 7 each) were prepared. Control rats (Uni-Nx) were also unilaterally nephrectomized but received a silicone rubber implant without DOCA and tap water to drink. After surgery, DOCA-salt–treated rats were fed by powdered diets (Purina Chow) containing rosiglitazone (5 mg/kg per day) or fenofibrate (100 mg/kg per day) and were offered 1% saline to drinking water. After 3 weeks of treatment, echocardiographic measurements and hemodynamic studies were performed and rats were then killed by decapitation.

Echocardiography
Echocardiography was performed after 3 weeks of treatment. The rats were anesthetized with fentanyl (50 µg/mL)/droperidol (2.5 mg/mL) vol/vol mix; the anterior chest was shaved, and echocardiography was performed with a Hewlett-Packard Sonos 5500 and a 15-MHz linear-array transducer on a warming pad to maintain normothermia. The transducer was placed on the left hemithorax, and care was taken to avoid excessive pressure on the thorax, which can induce bradycardia. Using the 2-dimensional, parasternal, short-axis imaging plan as guide, an LV M-mode tracing was acquired close to the papillary muscle level with a sweep speed of 150 mm/s. M-mode measurements of the LV end-diastolic and end-systolic internal diameter (LVIDd and LVIDs) and end-diastolic interventricular and LV posterior wall thickness (IVSd and LVPWd) were measured by using the leading-edge convention of the American Society of Echocardiography. Three to five beats were averaged for each measurement. End diastole and end systole were determined at the maximal LVIDd and at the peak of LVPW motion, respectively. Heart rate (HR) was calculated from two consecutive R-R intervals on the LV M-mode tracing. Ejection fraction (EF), fractional shortening (FS), and cardiac output (CO) were calculated as follows²⁰: EF (%)=[(LVDA-LVSA)/LVDA]x100, where LVDA is the LV diastolic area and LVSA is the LV systolic area. FS (%)=[(LVIDd-LVIDs)/LVIDd]x100; CO (L/min)=VTIxHRxAo/1000, where VTI is the velocity-time integral, HR is the aortic HR, and Ao is the aortic root area. LV mass was estimated (in mg) as previously described¹⁷: LV mass (mg)=[(LVIDd+IVSd+LVPWd)³-LVIDd³]x1.055, where 1.055 is the density of the rat myocardium (in mg/mm³). Relative wall thickness (RWT) was calculated as RWT=2xLVPWd/LVIDd.

Hemodynamic Study
Hemodynamic studies were performed the day after echocardiography and under fentanyl/droperidol anesthesia. A Millar ultraminiature catheter (1.5F nylon with single 2F pressure sensor) connected to a polygraph (PowerLab, AD Instruments) was inserted into the thoracic aorta, where pressure was recorded during 2 minutes, and then into the left ventricle. After a 5-minute stabilization period, LV pressure was recorded and then used for the determination of dP/dTmax and dP/dTmin, with the use of Chartview 4.1 software. The time constant (tau) of LV isovolumetric pressure decline was calculated as previously described as the time required for the cavity pressure at dP/dTmin to be reduced by half.²¹

Collagen Quantification
Hearts fixed in 4% paraformaldehyde at room temperature for 60 minutes were processed for paraffin embedding in an automated system (Shandon Citadel tissue processor). Serial sections (5 µm) of the median part of the left ventricle were dewaxed with ethanol and stained with Sirius red F3BA (0.5% in saturated aqueous picric acid) (Aldrich Chemical Co). Collagen density was evaluated throughout the inner third (subendocardial myocardium), the middle third (midmyocardium), and the outer third (subepicardial myocardium) of the circumference of the left ventricle. From each of 3 nonconsecutive serial sections (which allowed convergence of results), 10 fields in each region of the heart (magnification x20) were recorded. The severity of cardiac fibrosis was evaluated with an image analysis system (Northern Eclipse 5.0, EMPIX Imaging Inc). A single investigator unaware of the experimental groups performed the analysis.

Cardiac Prepro–ET-1 and ANF mRNA Levels
mRNA level of prepro–ET-1 and atrial natriuretic factor (ANF), a marker of cardiac hypertrophy, were studied by real-time PCR. Reverse transcription was performed using 2 µg RNA as previously described.²² Real-time PCR was performed with a Stratagene Mx4000 System for relative quantification of ventricular prepro–ET-1 and ANF mRNA. Primers were designed to generate short amplification products (147 bp for prepro–ET-1, 177 bp for ANF, and 107 bp for ribosomal protein S16, used as an internal standard), which spanned one intron region to detect contamination by genomic DNA. Primers for prepro–ET-1 were sense 5'-GCT GGT GGA GGG AAG AAA AC-3' and antisense 5'-CAC CAC GGG GCT CTG TAG TC-3', for ANF: sense 5'-AAC TGA GGG CTC TGC TCG CT-3' and antisense 5'-GTG ACA CAC CGC AAG GCT T-3', and for S16: sense 5'-AGG AGC GAT TTG CTG GTG TGG-3', and antisense 5'-GCT ACC AGG GCC TTT GAG ATG-3'. To validate our real-time PCR protocol, gene-specific standard curves for prepro–ET-1, ANF, and S16 were generated from serial 10-time dilutions of the cDNA. Linearity ranged from 1 to 1/1000 (for prepro–ET-1 and ANF) and 1/10 to 1/10000 (for S16). Slopes were similar (-3.49 for prepro–ET-1, -3.31 for ANF, and -3.47 for S16). Thus, 2 µL of 1/100 cDNA mixture was amplified by using specific primers. Real-time PCR was conducted with an initial denaturing interval (95°C, 15 minutes) and then 40 sequence cycles: 94°C (30 seconds), 58°C (45 seconds), and 72°C (30 seconds), using the Quantitect SYBR Green PCR Kit (Qiagen) and a final 0.5 µmol/L concentration of primers (run in duplicate). Amplification products were electrophoresed on 1% agarose gels containing ethidium bromide and visualized with UV light to check the fragment length and the absence of nonspecific products that could interfere with fluorescence signal produced by SYBR Green (not shown). A melting curve analysis was also performed to check absence of formation of primer-dimers. Samples from Uni-Nx cDNAs were used as calibrators and variations of prepro–ET-1, ANF, or S16 were calculated as a relative quantity compared with this group. Results are expressed as the ratio between the gene of interest and S16 relative quantities.

Data Analysis
Data are presented as mean±SEM. One-way ANOVA was followed by a Student-Newman-Keuls test. A value of P<0.05 was considered significant.

	Results

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Blood Pressure and Body Weight
Mean aortic blood pressure was increased by 36 mm Hg in DOCA-salt rats after 3 weeks of treatment, compared with Uni-Nx (Table 1). Rosiglitazone prevented this increase, whereas a slight trend to decrease in mean aortic blood pressure induced by fenofibrate did not achieve statistical significance. Neither rosiglitazone nor fenofibrate administrated alone modified blood pressure. Similar effects were observed for systolic and diastolic blood pressures. Pulse pressure was increased in DOCA-salt rats by 22 mm Hg, compared with Uni-Nx. However, neither rosiglitazone nor fenofibrate prevented this increase. Both rosiglitazone and fenofibrate prevented the body weight loss observed in DOCA-salt rats and had no effect in Uni-Nx rats (Table 2). Heart weight and heart weight/tibia length tended to increase in DOCA-salt rats and were augmented significantly in rosiglitazone-treated rats and, to a lesser extent, in those treated with fenofibrate. No change was observed in tibia length.

View this table: [in this window] [in a new window]   TABLE 1. Hemodynamic Parameters Measured by Millar Probe

View this table: [in this window] [in a new window]   TABLE 2. Heart and Body Weight

Cardiac Hypertrophy
After 3 weeks of treatment, echocardiography showed concentric cardiac hypertrophy in DOCA-salt rats. IVSd, LVPWd, and relative wall thickness were increased, and LVIDd, LVIDs decreased (Table 3). The calculated mass of LV tended to increase and the LV mass/tibia length ratio was significantly higher when compared with Uni-Nx. Coadministration of rosiglitazone or fenofibrate in DOCA-salt rats improved cardiac geometry by restoring LVIDd and LVIDs to values comparable to Uni-Nx rats. However, neither PPAR activator prevented thickening of IVSd and LVPWd. ANF was used as a marker of cardiac hypertrophy, and its ventricular mRNA expression was dramatically increased in the left ventricle of DOCA-salt rats compared with Uni-Nx (P<0.01, Figure 1). Rosiglitazone and fenofibrate did not prevent this increase in DOCA-salt rats and tended to increase ANF mRNA expression in Uni-Nx rats.

View this table: [in this window] [in a new window]   TABLE 3. Cardiac Geometry

View larger version (17K): [in this window] [in a new window]   Figure 1. Relative quantification of prepro–ET-1 and ANF mRNA content in the cardiac left ventricle normalized to the housekeeping gene of ribosomal protein S16 (run in duplicate), n=4 per group. Results are presented as mean±SEM. Uni-Nx indicates unilaterally nephrectomized control; ROSI, rosiglitazone; FEN, fenofibrate. *P<0.05, P<0.01 vs Uni-Nx, P<0.05 vs DOCA-salt, 1-way ANOVA.

Cardiac Function
Compared with Uni-Nx rats, cardiac function was not altered in DOCA-salt rats, as suggested by the different functional parameters assessed by echocardiography (FS, EF, and CO, Figure 2). Diastolic function was assessed with the use of a Millar catheter. DOCA-salt rats presented an increase of the time constant tau, suggesting a decrease in ventricular relaxation, resulting from diastolic dysfunction affecting LV filling (Table 1). Rosiglitazone and fenofibrate did not improve this parameter. No other functional difference was observed in treated animals. Neither dP/dTmax, dP/dTmin, nor LV end-diastolic pressure were altered by DOCA-salt and/or rosiglitazone or fenofibrate.

View larger version (50K): [in this window] [in a new window]   Figure 2. Echocardiographic parameters determined in anesthetized rats after 3 weeks of treatment. Results are presented as mean±SEM; n=6 per group.

Collagen Content
Sirius red staining revealed an increased interstitial collagen content in the endocardium, midmyocardium, and epicardium of DOCA-salt rats (Figure 3). Coadministration of rosiglitazone or fenofibrate partially prevented this increase in the three myocardial regions in DOCA-salt rats.

View larger version (24K): [in this window] [in a new window]   Figure 3. Quantification of interstitial collagen content in the left ventricle. Results are presented as mean±SEM; n=6 per group. *P<0.001 vs Uni-Nx, P<0.01 or P<0.001 vs DOCA-salt, 1-way ANOVA.

Ventricular Prepro–ET-1 mRNA Levels
Real-time PCR analysis (Figure 1) revealed a 3-fold increase in prepro–ET-1 mRNA level in the heart of DOCA-salt rats. Both rosiglitazone and fenofibrate prevented this increase and had no significant effect on the basal levels in Uni-Nx animals.

	Discussion

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Our results provide evidence for a beneficial effect of rosiglitazone and fenofibrate on cardiac fibrosis and remodeling in DOCA-salt rats associated with an inhibitory effect on cardiac ET-1 production. Both PPAR activators failed to prevent cardiac hypertrophy but prevented concentric remodeling in these animals.

DOCA-salt rats had cardiac hypertrophy (as characterized by echocardiography and cardiac ANF content) and increased myocardial fibrosis associated with enhanced prepro–ET-1 mRNA production. We have previously shown that coadministration of an ET_A receptor antagonist prevented the development of cardiac fibrosis but not hypertrophy associated with decreased TGF-ß and redox-sensitive proinflammatory proteins such as NF-B,^3,7 indicating independent mechanisms involved in development of cardiac fibrosis and hypertrophy in this model. Our present findings strengthen and extend these observations, since inhibition of cardiac ET-1 production by rosiglitazone and fenofibrate was associated with decreased cardiac fibrosis. The absence of effect of fenofibrate on blood pressure suggests that this mechanism is blood pressure–independent. These results are consistent with previous in vitro and in vivo data showing an inhibitory effect of PPAR- and PPAR- activation on ET-1 production^18,22 and an ET-1–mediated stimulation of collagen synthesis by cardiac fibroblasts.⁶ We and others have shown that ET-1 stimulates the Na/H exchanger,²³ which may be involved in development of fibrosis in DOCA-salt rats.²⁴ Thus, inhibition of endogenous ET-1 production by PPAR agonists may also prevent Na/H exchanger activation. Taken together, our data underscore the role of ET-1 in the development of cardiac fibrosis. However, because of the pleiotropic role of PPAR activators, we cannot exclude an ET-1–independent mechanism or distinct mechanisms of action for both PPAR isoforms. Indeed, PPAR- activators may prevent cardiac fibrosis through inhibition of expression of TGF-ß, a profibrotic agent that has also been shown to activate ET-1 production in vascular cells.^7,25,26 As potent anti-inflammatory factors, PPAR- may also modulate matrix metalloproteinase activity through several mechanisms such as AP-1 or TNF- inhibition.^11,18,27 On the other hand, PPAR-^-/- mice present enhanced cardiac fibrosis.²⁸ In vitro studies have suggested that PPAR- agonists could prevent MMP-9 expression by inhibiting Il-1–induced activation of NF-B.²⁹ Despite a decrease in cardiac prepro–ET-1 mRNA, both fenofibrate and rosiglitazone failed to prevent cardiac hypertrophy, as measured by echocardiography, in DOCA-salt rats. Several possibilities may explain this result. Beneficial effects of ET system blockade on cardiac hypertrophy may be blood pressure–dependent, as suggested by a recent study³⁰ showing benefits of ET_A blockade associated with pronounced decrease in blood pressure on development of LV hypertrophy. We previously showed an absence of effect of ET_A receptor blockade, associated with a modest antihypertensive effect, on development of cardiac hypertrophy in DOCA-salt rats, suggesting a weak role for ET-1 in this process.^3,7 Our present study provides additional evidence of a minor role of ET-1 on the development of cardiac hypertrophy, since both treated groups had blunted cardiac ET-1 levels together with normal (rosiglitazone) or elevated (fenofibrate) blood pressure. Although only rosiglitazone decreased systolic blood pressure in DOCA-salt rats, pulse pressure, another predictive factor for LV hypertrophy, was not affected by either treatment (Table 1). This could explain in part the absence of effect of either treatment on cardiac hypertrophy. Indeed, we previously showed that neither rosiglitazone nor fenofibrate prevented vascular stiffening in the same model.²² As discussed below, the DOCA-salt rat is a model of severe hypertension associated with activation of other mechanisms, such as the sympathetic system and vasopressin, which may be involved in the development of cardiac hypertrophy.³¹ As well, side effects such as fluid retention have been reported with glitazones³² and could explain the worsening of cardiac hypertrophy induced by rosiglitazone.

As a limitation of this study, it should be pointed out that hormonal systems other than ET-1 may contribute to cardiovascular damage in DOCA-salt rats. Indeed, angiotensin type-1 receptor antagonists may regress cardiac hypertrophy independent of blood pressure–lowering effects in this model.³³ Vasopressin plays a role in the development of hypertension³⁴ in our model and has been described as a hypertrophic agent on cardiac myocytes.^31,35 Recent data indicate that short-term treatment with fenofibrate prevents cardiac fibrosis and ET-1 production in a model of aortic banding in rats.³⁶ Moreover, PPAR- activators (troglitazone and pioglitazone) partially prevented cardiac hypertrophy and ET-1 overexpression in the same model.³⁷ However, these observations were performed after aortic banding for only 24 hours and could be attributed to tissue edema rather than true hypertrophy. Despite major methodological differences (especially duration of treatment), our data demonstrate that the inhibition of ET-1 production in vivo persists during long-term treatment with PPAR- and PPAR- agonists.

Despite concentric remodeling and enhanced fibrosis, cardiac function was not impaired in DOCA-salt rats after 3 weeks. With respect to the time course of development of cardiac dysfunction in this model, our observations may reflect early diastolic dysfunction, as suggested by the increase of tau, associated with enhanced LV fibrosis. Indeed, DOCA-salt rats have been recently described to present impaired LV diastolic function with increased LV end-diastolic pressure at 8 weeks of treatment.³⁰ However, despite a significant decrease of LV fibrosis, both rosiglitazone and fenofibrate failed to improve diastolic dysfunction, which could be attributed to only partial effects on hemodynamic parameters (ie, systolic arterial pressure and pulse pressure) or to residual fibrosis.

Perspectives
Our data provide evidence for antifibrotic action of rosiglitazone and fenofibrate in DOCA-salt rats associated with inhibition of LV ET-1 content. Despite a lack of effect on cardiac hypertrophy, concentric remodeling was prevented by both PPAR- and PPAR- activators. Thus, the use of combined PPAR- and PPAR- activators could represent a promising approach in the prevention of fibrosis contributing to cardiac remodeling and heart failure.

	Acknowledgments

 
This study was supported by grant 37917 and a group grant to the Multidisciplinary Research Group on Hypertension, both from the Canadian Institutes of Health Research, and a grant from the Fondation des maladies du coeur du Québec. M. Iglarz is supported by a fellowship from Fondation pour la Recherche Médicale of France. The authors are grateful to Dr Ping Yue, Manon Laprise, André Turgeon, Suzanne Diébold, and Annie Vallée for excellent technical support.

Received May 5, 2003; first decision May 27, 2003; accepted June 12, 2003.

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