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CARDIOVASCULAR

Effects of Resveratrol (trans-3,5,4'-Trihydroxystilbene) Treatment on Cardiac Remodeling following Myocardial Infarction

Research Center (B.B., A.M., R.C., H.G., F.P., J.-C.T., S.N.) and Department of Physiology (A.C.), Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (B.B., N.E., T.E.H., S.N.)

Received June 21, 2007; accepted September 14, 2007.

	Abstract

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Resveratrol (RES; trans-3,5,4'-trihydroxystilbene) has been shown to improve health and slow the progression of disease in various models. Several cardioprotective mechanisms have been identified including antioxidant, anti-inflammatory, and antifibrotic actions. Each of these actions is thought to have the ability to attenuate the pathophysiology underlying the deleterious cardiac structural remodeling that results from acute myocardial infarction (MI). Therefore, we evaluated the effect of resveratrol treatment on the progression of cardiac remodeling after MI. Four groups of rats (sham, n = 6; sham + RES, n = 21; MI, n = 26; MI + RES, n = 24) were treated for 13 weeks, starting 7 days before ligation of the left anterior descending coronary artery. Serial transthoracic echocardiography revealed that resveratrol had no effect on MI-induced left-ventricular and left-atrial dilatation or reduction in left-ventricular fractional shortening. Consistent with these findings, resveratrol did not improve the deterioration of hemodynamic function or reduce infarct size at 12 weeks post-MI. Resveratrol-treated animals did, however, show preserved cardiac contractile reserve in response to dobutamine administration. Radioligand binding revealed that MI reduced -adrenergic receptor density. Resveratrol administration increased -adrenoceptor density, so that resveratrol-treated MI rats had -adrenoceptor densities similar to normal rats. Real-time reverse transcription-polymerase chain reaction revealed that MI-induced changes in sarcoplasmic reticulum Ca²⁺-ATPase 2 and transforming growth factor -1 expression were unaltered by resveratrol, whereas MI-induced increases in atrial natriuretic factor (ANF) and connective tissue growth factor (CTGF) expression were attenuated. Resveratrol treatment does not improve cardiac remodeling and global hemodynamic function post-MI but does preserve contractile reserve and attenuate ANF and CTGF up-regulation.

	Materials and Methods

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Animal Handling. Animal care procedures were approved by the institutional animal research ethics committee and were consistent with the guidelines of the National Institutes of Health (Institute of Laboratory Animal Resources, 1996). Male Sprague-Dawley rats weighing between 200 and 250 g were randomly assigned to four groups: sham surgery (sham group), sham surgery with 7 days of resveratrol pretreatment (sham + RES group), and MI surgery with (MI + RES group) and without (MI group) resveratrol pretreatment. Resveratrol (obtained from Royalmount Pharma, Montreal, Canada) was administered to sham + RES and MI + RES groups orally in the rat chow, and consumption was maintained at a constant rate (17 mg/kg/day) throughout the experimental protocol (days –7 through 84). Left anterior descending (LAD) coronary artery ligation (MI and MI + RES groups) or sham surgeries (sham and sham + RES groups) were performed in parallel as described previously (Drapeau et al., 2005). Body weight, heart rate, and drug consumption were monitored regularly and were not different among the groups at any time points. Twelve weeks after LAD ligation or sham surgery, all animals were euthanized, and hearts were removed and dissected into left atrium (LA), right atrium, left ventricular (LV) free wall, right ventricular free wall, interventricular septum, and scar. Scars were measured for surface area to assess MI size (Lapointe et al., 2003), and all portions of the heart were weighed individually, then snap-frozen in liquid nitrogen for biochemical analysis.

Echocardiographic Assessment. Transthoracic echocardiography was performed on all animals at baseline (day –7) and again in all surviving animals post-MI at days 2, 7, 28, 56, and immediately before hemodynamic assessment and sacrifice on day 84. Measurements were made in isoflurane-anesthetized rats with a 10S phased-array probe (11.5 MHz) and a Vivid 7 Dimension system (GE Healthcare Ultrasound, Horten, Norway) as described previously (Asselin et al., 2007). The LV was imaged with a short-axis view at the midpapillary muscle level. Left ventricular end-diastolic diameter (LVDD) was defined as the largest LV diameter, left ventricular end-systolic diameter was defined as the smallest LV diameter, and the fractional shortening was calculated as [(LVDD – left ventricular end-systolic diameter)/LVDD] x 100. The LA was imaged in the parasternal long-axis view at the level of the aortic valve, and LA diameter was defined as the distance between the posterior wall of the aorta and the posterior wall of the LA during cardiac systole. The average of three consecutive cardiac cycles was used for all measurements. Special care was taken to obtain similar imaging planes on the baseline and follow-up studies. Heart rate was simultaneously recorded by electrocardiogram. The operator was blinded to treatment assignment.

Hemodynamic Assessment and Dobutamine Stress Test. Eighty-four days after LAD ligation or sham surgery, hemodynamic measurements were performed on all surviving animals. Measurements were made in spontaneously breathing, anesthetized animals using a Millar microtip pressure transducer, advanced through the carotid artery to the LV as described previously (Drapeau et al., 2005). All measurements were made by a single experienced operator, blinded to treatment group. Left ventricular end-diastolic pressure (LVEDP), maximum generated pressure (P_max), and maximal rate of pressure development (+dP/dt_max) and relaxation (–dP/dt_min) were each measured. Left ventricular contractile reserve was assessed following baseline hemodynamic study by i.v. administration of the -adrenergic agonist dobutamine at a dose of 5 µg/kg b.wt./min for 3 min.

-Adrenergic Radioligand Binding. Membrane preparations were generated from noninfarcted LV tissue samples from all groups (n = 6–8/group), and assays for total -adrenergic receptor (AR) binding density were performed by a blinded observer as described previously (Lemire et al., 1998). AR density was calculated from binding experiments with [¹²⁵I]cyanopindolol as a radioligand. Membrane fractions were labeled with 300 pM [¹²⁵I]cyanopindolol at near-saturating concentrations. Nonspecific binding was defined with 10 µM alprenolol.

Real-Time RT-PCR. Total RNA was extracted from noninfarcted LV tissues (n = 6–8/group) as described previously (Mercier et al., 2002). Real-time RT-PCR (SYBR Green, predesigned primers and Mastermix from Applied Biosystems, Foster City, CA) measurements were made by an observer blinded to treatment group to determine expression of atrial natriuretic factor (ANF), SERCA-2, collagen (Col) 1, Col3, transforming growth factor -1 (TGF₁), and connective tissue growth factor (CTGF) mRNA levels. Expression values were normalized to the reference gene -actin.

Statistical Analysis. Data are presented as mean ± S.E.M. For infarct size data, statistical significance was assessed using the Student's t test. Clinical characteristics, hemodynamics, receptor binding, and real-time RT-PCR data were analyzed by two-way analysis of variance (ANOVA), and echographic data were analyzed by two-way repeated measures ANOVA using mixed model methodology with time as a repeated main factor. When two-way ANOVA revealed a significant interaction between factors, contrasts were applied to compare groups. A two-tailed P value < 0.05 was considered statistically significant. All analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, NC).

	Results

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Clinical and Morphologic Characteristics. Three months after surgery, both the MI and MI + RES animals showed features of cardiac remodeling compared with the corresponding sham groups (Table 1). Mortality was not different between MI groups, and all deaths occurred within the first 24 h post-MI. Heart weight/body weight ratio was similarly increased in MI and MI + RES groups compared with the sham-operated groups because of increased weights in the left atrium, right atrium, right ventricular free wall, and interventricular septum. Left ventricular free wall weight was unchanged by MI, probably because of the opposing effects on left ventricular mass of infarct scar thinning and myocardial hypertrophy. Resveratrol had no effect on MI-induced elevation of LVEDP. LAD ligation produced large infarcts with scar surface area >35 mm² (Lapointe et al., 2003), and scar size was unchanged by resveratrol treatment (Fig. 1).

View larger version (26K): [in this window] [in a new window]   Fig. 1. Mean ± S.E.M. infarct size at 12 weeks post-MI, expressed as percentage of scar weight to heart weight (A) and scar surface area (B) in MI and MI + RES rats.

View larger version (24K): [in this window] [in a new window]   Fig. 2. Echocardiographic analyses showing the development of LV (A and B) and LA (D) dilatation with a concomitant reduction in fractional shortening (C) in MI and MI + RES animals. Resveratrol treatment had no effect on any echocardiographic parameters. Data are mean ± S.E.M., *, P < 0.05 MI versus sham; , P < 0.05 MI + RES versus sham + RES.

Hemodynamic Measurements. Hemodynamic measurements were recorded at 12 weeks post-MI. In agreement with the echocardiographic data, MI rats showed signs of systolic and diastolic dysfunction, with significant reductions in +dP/dt_max (18 ± 4%) and –dP/dt_min (24 ± 4%), as well as P_max (13 ± 3%) compared with the sham group. There was no statistically significant baseline difference in sham animals with or without resveratrol, and resveratrol treatment did not improve hemodynamic variables in infarcted animals (Fig. 3).

View larger version (27K): [in this window] [in a new window]   Fig. 3. Baseline hemodynamic measurements showing mean ± S.E.M. LV +dP/dtmax (A), –dP/dtmin (B), and Pmax (C) among treatment groups. Resveratrol treatment had no basal effect and did not attenuate MI-induced reductions in +dP/dtmax, –dP/dtmin, or Pmax. **, P < 0.01 MI versus sham; ***, P < 0.001 MI versus sham; , P < 0.05 MI + RES versus sham + RES; , P < 0.01 MI + RES versus sham + RES; , P < 0.001 MI + RES versus sham + RES.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Contractile reserve demonstrated by change in +dP/dtmax (A), –dP/dtmin (B), and Pmax (C) in response to dobutamine stress test. Resveratrol treatment had no basal effect and abolished the MI-induced reductions in +dP/dtmax, –dP/dtmin, and Pmax. Data are mean ± S.E.M., *, P < 0.05 MI versus sham; ***, P < 0.001 MI versus sham.

View larger version (23K): [in this window] [in a new window]   Fig. 5. Total AR binding. RES treatment increases AR density, opposing the -receptor-suppressing effect of MI. Data are mean ± S.E.M., n = 6 to 8/group, **, P < 0.01 main effect of MI; , P < 0.01 main effect of RES.

View larger version (32K): [in this window] [in a new window]   Fig. 6. Expression of the cardiac remodeling-related genes ANF (A), SERCA-2 (B), Col1 (C), Col3 (D), TGF1 (E), and CTGF (F), all normalized to the reference gene, -actin. Data are mean ± S.E.M., n = 6 to 8/group, *, P < 0.05 MI versus sham; **, P < 0.01 MI versus sham; , P < 0.05 MI + RES versus sham + RES.

	Discussion

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Main Findings. The present study has demonstrated that resveratrol treatment does not influence 12-week post-MI infarct size in rats. Echocardiographic assessment showed that resveratrol does not alter the course of postinfarction functional remodeling. Furthermore, treatment did not improve global hemodynamic function. All of these measurements are consistent in showing a lack of effect of resveratrol on basal myocardial function and remodeling consequences of MI. However, resveratrol did preserve the contractile response to dobutamine administration, possibly because of an increase in AR density resulting from resveratrol administration. In addition, resveratrol attenuated the MI-induced up-regulation of ANF and CTGF mRNA levels. Several cardioprotective mechanisms of resveratrol treatment have been proposed, thus providing a strong rationale to hypothesize that resveratrol administration would ameliorate LV contractility and attenuate the progression of remodeling post-MI. Although resveratrol treatment failed to result in significant overall improvement, the preservation of contractile reserve observed under dobutamine stress may represent a useful form of cardioprotection. Several previous animal studies suggested that resveratrol may be a promising therapeutic agent for the prevention of ischemic myocardial damage; our findings suggest caution in the application of resveratrol to achieve protective effects against MI-induced cardiac remodeling.

Potential Mechanisms. Radioligand binding confirmed the well established observation that MI reduces AR density (Brodde, 1993), and resveratrol administration was found to return values for receptor binding of MI rats to baseline. Taken together with hemodynamic data in response to dobutamine, resveratrol treatment appears to globally increase AR binding density, which may become functionally important only in the presence of compromised LV function, such as post-MI. This is consistent with the notion that resveratrol treatment contributes to a preservation of cardiac contractile reserve, despite not attenuating remodeling and baseline hemodynamic function. Only a very limited number of studies have examined the interaction of resveratrol with -adrenergic signaling, and although a few have described direct time- and dose-dependent activation of adenylyl-cyclase (El Mowafy and Alkhalaf, 2003; Blumenstein et al., 2005) the lack of positive inotropic effects in sham + RES animals under dobutamine stress argues against this potential mechanism. Alternatively, resveratrol may cause up-regulation of "spare" ARs, that is, receptors not required for the production of the maximal inotropic response (Brown et al., 1992; Lee et al., 1999), particularly in light of the fact that resveratrol-induced increases in AR density failed to enhance the dobutamine response in sham animals. Additional (spare) receptors that are not coupled to a functional response under physiological conditions may be of functional importance only in the presence of MI, when the number of ARs are critically reduced.

Relation to Previous Studies. We found that resveratrol treatment did not reduce infarct size, echocardiographic, or hemodynamic indices of cardiac remodeling post-MI. This finding is somewhat discordant with reports in which resveratrol-treated rats sustained smaller infarcts and were protected from MI-induced hemodynamic dysfunction (Kaga et al., 2005; Fukuda et al., 2006). These improvements may be limited to early remodeling because measurements were recorded at 4 days (Kaga et al., 2005) and 3 weeks (Fukuda et al., 2006) post-MI in previous studies; however, even our early echocardiographic indices of LV function, obtained at 2, 7, and 28 days post-MI, failed to show benefit. The same studies also report preservation of contractile reserve, which we did observe at 12 weeks post-MI. As seen in the present study, Hale and Kloner (2001) also found that resveratrol did not improve infarct size. The comparable infarct sizes in MI and MI + RES rats permitted us to compare cardiac remodeling for a given infarct size. Similar doses of resveratrol administered i.v., 10 min before LAD ligation, were found to reduce the incidence of ventricular arrhythmia/fibrillation, consequently reducing immediate mortality by 40% compared with saline-treated controls (Zhang et al., 2006). However, we did not observe a mortality difference in resveratrol-treated rats. Discrepancies in survival effects may be attributable to route of administration and/or a longer observation period in the present study.

The down-regulation of SERCA-2 mRNA in both MI and MI + RES groups is consistent with the observed ventricular dysfunction and elevated LVEDP because SERCA-2 down-regulation is believed to be an important contributor to post-MI LV dysfunction (Kim et al., 2002). Likewise, TGF₁ up-regulation is a well established feature in MI-induced cardiac remodeling (Hao et al., 1999), and the observation of comparable values in MI and MI + RES groups is consistent with a lack of difference in remodeling progression postinfarct. Resveratrol treatment attenuated the up-regulation of ANF and CTGF mRNAs. TGF₁ is a well established profibrotic factor centrally involved in postinfarct remodeling, inducing increases in both ANF (Huang et al., 2004) and CTGF (Chen et al., 2000) expression. Accordingly, it might be expected that each member of this axis (including TGF₁) be strongly elevated at 12 weeks post-MI; however, our results are consistent with the observation that CTGF is up-regulated and remains elevated at 12 weeks post-MI, compared with collagen I, collagen III, and TGF₁, which peak early and return to near-baseline values (Chen et al., 2000). CTGF has been shown to be important in the progression of cardiac remodeling (Ahmed et al., 2005; Dean et al., 2005; Koitabashi et al., 2007), up-regulated specifically in cardiac fibroblasts following MI (Ohnishi et al., 1998), and is a key mediator of fibroblast function (Ahmed et al., 2004). The CTGF-blocking effect by resveratrol we observed in vivo may similarly contribute to the inhibition of cardiac fibroblast proliferation and differentiation previously observed in vitro (Olson et al., 2005; Wang et al., 2007). However, the prevention of CTGF up-regulation did not translate into beneficial anti-remodeling actions, suggesting that at least in the present system, CTGF expression changes may not play a major role in remodeling.

Limitations of the Study. The timing and dosing regime may influence the effectiveness of resveratrol treatment. Das and Maulik (2006) have suggested that there exists a dose-dependent bimodality to the actions of resveratrol, potentially because of wide-ranging differences in tissues in pharmacokinetics, bioavailability, and metabolism. We elected to pretreat rats with a dose that has been well characterized (Wenzel and Somoza, 2005; Wenzel et al., 2005) and used in other studies demonstrating important biological consequences (Martin et al., 2004; Baur et al., 2006). This dose far exceeds the resveratrol intake associated with the content of red wine and may not translate directly in man. Because we analyzed samples obtained from rats euthanized at the end of the study and did not add multiple additional groups for euthanasia at various time points, we cannot be sure whether resveratrol acts to attenuate ANF and CTGF up-regulation or causes a more rapid return to baseline values.

In the present study, only pressure-derived indices of hemodynamic function have been assessed. It is possible that more sophisticated parameters (such as end-systolic elastance, preload recruitable stroke work, pressure-volume area, mechanical efficiency) would reveal beneficial effects of resveratrol treatment. We also cannot rule out the potential for resveratrol to be used as an adjunct in combination therapy, for example with statins, to more greatly attenuate cardiac remodeling (Penumathsa et al., 2007).

We observed an interesting effect of resveratrol to increase AR density and to prevent the loss of response to dobutamine in MI rats. The dobutamine response could be affected by changes in G_s or opposing G_i protein expression, the function and/or expression of adenylyl cyclase, the number and affinity of ARs, and a variety of other factors. The increase in AR density that we observed with resveratrol could explain the preserved dobutamine response in MI + RES rats, but other changes in the -adrenergic signaling system cannot be excluded. Although a detailed analysis of the effects of resveratrol on -adrenergic signaling would potentially be of great interest, it is beyond the scope of the present study.

	Acknowledgements

 
We thank Nathalie L'Heureux and Chantal St-Cyr for technical assistance and France Thériault for secretarial support.

	Footnotes

 
This work was supported by the Canadian Institutes of Health Research and by the Quebec Heart and Stroke Foundation. B.B. received a Canadian Institutes of Health Research M.D./Ph.D. studentship. A.C. is a Chercheur-Boursier National of the "Fonds de la Recherche en Santé du Québec." T.E.H. is a senior scholar of the Fonds de la Recherche en Santé du Québec and is supported by grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Québec.

B.B. and A.M. contributed equally to this work.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.107.127548.

ABBREVIATIONS: RES, resveratrol, trans-3,5,4'-trihydroxystilbene; MI, myocardial infarction; LAD, left anterior descending; LA, left atrium; LV, left ventricle; LVDD, left ventricular end-diastolic diameter; LVEDP, left ventricular end-diastolic pressure; P_max, maximum generated pressure; +dP/dt_max, maximal rate of pressure development; –dP/dt_min, maximal rate of pressure relaxation; AR, -adrenergic receptor; RT, reverse transcription; PCR, polymerase chain reaction; ANF, atrial natriuretic factor; SERCA-2, sarcoplasmic reticulum Ca²⁺-ATPase 2; Col, collagen; TGF₁, transforming growth factor -1; CTGF, connective tissue growth factor; ANOVA, analysis of variance; DFn, degree of freedom in the numerator; DFd, degree of freedom in the denominator.

Address correspondence to: Stanley Nattel, 5000 Belanger St. E., Montreal, Quebec H1T 1C8, Canada. E-mail: stanley.nattel{at}icm-mhi.org

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