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Endocrinology Vol. 149, No. 11 5828-5834
Copyright © 2008 by The Endocrine Society

Transforming Growth Factor-β Blockade Down-Regulates the Renin-Angiotensin System and Modifies Cardiac Remodeling after Myocardial Infarction

Leigh J. Ellmers, Nicola J. A. Scott, Satyanarayana Medicherla, Anna P. Pilbrow, Paul G. Bridgman, Timothy G. Yandle, A. Mark Richards, Andrew A. Protter and Vicky A. Cameron

Christchurch Cardioendocrine Research Group (L.J.E., N.J.A.S., A.P.P., T.G.Y., A.M.R., V.A.C.), Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch 8140, New Zealand; SCIOS Inc. (S.M., A.A.P.), Fremont, California 94555; and Department of Cardiology (P.G.B.), Christchurch Hospital, Christchurch 8011, New Zealand

Address all correspondence and requests for reprints to: Dr. L. J. Ellmers, Ph.D., Department of Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch 8140, New Zealand. E-mail: leigh.ellmers{at}chmeds.ac.nz.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
After myocardial infarction (MI), the heart may undergo progressive ventricular remodeling, resulting in a deterioration of cardiac function. TGF-β is a key cytokine that both initiates and terminates tissue repair, and its sustained production underlies the development of tissue fibrosis, particularly after MI. We investigated the effects of a novel orally active specific inhibitor of the TGF-β receptor 1 (SD-208) in an experimental model of MI. Mice underwent ligation of the left coronary artery to induce MI and were subsequently treated for 30 d after infarction with either SD-208 or a vehicle control. Blockade of TGF-β signaling reduced mean arterial pressure in all groups. SD-208 treatment after MI resulted in a trend for reduced ventricular and renal gene expression of TGF-β-activated kinase-1 (a downstream modulator of TGF-β signaling) and a significant decrease in collagen 1, in association with a marked decrease in cardiac mass. Post-MI SD-208 treatment significantly reduced circulating levels of plasma renin activity as well as down-regulating the components of the cardiac and renal renin-angiotensin system (angiotensinogen, angiotensin converting enzyme, and angiotensin II type I receptor). Our findings indicate that blockade of the TGF-β signaling pathway results in significant amelioration of deleterious cardiac remodeling after infarction.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MYOCARDIAL INFARCTION (MI) often leads to adverse ventricular remodeling resulting in changes in size, shape, and function of the heart and the subsequent development of heart failure. The effects of cardiac structural and molecular remodeling include marked ventricular dilatation, wall thinning at the site of infarction, and myocardial fibrosis both at, and remote to, the site of MI. Increased myocardial collagen and abnormal matrix structure results in myocardial stiffness, leading to ventricular systolic and diastolic dysfunction (1). Fibrosis therefore is an integral feature of the failing heart.

Transforming growth factor-β1 (TGF-β1) is a profibrotic cytokine responsible for inducing the proliferation of cardiac fibroblasts, their phenotypic transformation to myofibroblasts, and the deposition of extracellular matrix (ECM) (2), particularly collagen types I and III (3). TGF-β1 mRNA is up-regulated in animal models of MI and pressure overload (4, 5, 6). Moreover, transgenic mice overexpressing TGF-β1 exhibit cardiac hypertrophy, which is characterized by both interstitial fibrosis and hypertrophy of cardiomyocytes (7, 8).

The renin-angiotensin system (RAS) is also a key mediator involved in the pathogenesis of cardiac remodeling and failure (9, 10). Angiotensin II (Ang II) stimulates fibroblast proliferation, collagen synthesis, and the expression of ECM proteins via activation of the Ang II type I receptor (AT1R) (11). Numerous clinical trials (12, 13) and animal studies (14, 15) have shown Ang II inhibition using angiotensin-converting enzyme (ACE) inhibitors or AT1R blockade reverses or prevents ventricular remodeling and improves survival. Evidence from many studies also indicate a functional link between Ang II and TGF-β1 in the heart. TGF-β1 mRNA and protein are up-regulated by Ang II in myofibroblasts and cardiac fibroblasts (16, 17), and Ang II antagonists have been shown to inhibit the gene expression of TGF-β1 and ECM in cardiac tissue (18). In a seminal study, Schultz et al. (19) demonstrated that Ang II could not induce hypertrophy in mice lacking the TGF-β1 gene. This study provided the first direct evidence that Ang II-induced cardiac hypertrophy is mediated by TGF-β1. Collectively, these studies indicate TGF-β1 acts downstream of Ang II and is responsible for promoting fibrosis and hypertrophy in the heart.

TGF-β1 interacts with a series of serine/threonine receptors termed activin receptor-like kinases (ALK) (20). TGF-β receptor I (ALK5) acts downstream of the TGF-β type II receptor, and these receptors are involved in activating intracellular phosphorylated mothers against decapentaplegic (Smad) proteins as well as TGF-β-activated kinase-1 (TAK1), p38 MAPK, Erk, and c-Jun N-terminal kinase, which mediate the biological effects of TGF-β1 (21). ALK5 is a specific receptor for TGF-β and is responsible for the phosphorylation of Smad2 and Smad3 (22).

In this study, we hypothesized that treatment with a potent orally active selective inhibitor of ALK5 kinase activity (SD-208) (22) after MI would block TGF-β activity and attenuate the development of cardiac hypertrophy and fibrosis after infarction. We then examined the effects of SD-208 treatment on gene expression of key molecules involved in ventricular remodeling.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Myocardial Infarction
All protocols were approved by the Animal Ethics Committee of the University of Otago (Dunedin, New Zealand). The technique of left coronary artery ligation was used to induce MI in C57BL/6 male mice. Thirty-two 12-wk-old mice underwent either ligation of the coronary arteries (n = 16) or sham control surgeries (thoracotomy without coronary ligation; n = 16).

Anesthesia was induced with 75 mg/kg Ketamine (Phoenix Pharm, Auckland, New Zealand) and 1 mg/kg Domitor (Medetomidine hydrochloride; Orion Corporation, Espoo, Finland) by sc injection. The chest was shaved and endotracheal intubation carried out under direct laryngoscopy. Mice were ventilated at a rate of 107 breaths/min, with a tidal volume of 1.5 ml. A left lateral thoracotomy was performed followed by ligation of the left coronary artery midway between the left atrium and the apex of the left ventricle. Successful ligation was evidenced by blanching and dyskinesis of the distal myocardium. After infarction, the chest was closed and inflation of the lungs maintained by application of positive end expiratory pressure through the ventilator. Animals were administered Antisedane 1 mg/kg (Atipamezole hydrochloride; Orion Corporation, Espoo, Finland), an antagonist of the anesthetic Domitor, and extubated when spontaneous respirations returned. In the sham surgeries, a left lateral thoracotomy was performed and the pericardium opened (without coronary artery ligation) before closing the chest. The mice were observed in a temperature-controlled environment until full recovery and then returned to the animal holding facility in which they were given standard chow and water ad libitum.

After return to the home cage, each of the two groups of mice-infarcted and sham controls were randomly divided into two further groups, receiving either the TGF-β antagonist SD-208 (SCIOS Inc., Fremont, CA; n = 8) or vehicle control (n = 8). SD-208, a novel 2,4-disubstituted pteridine derivative, is a potent orally active selective TGF-β RI kinase inhibitor (22). SD-208 (60 mg/kg·d) was administered orally in the dietary supplement Complan (Heinz Watties, New Zealand). Dosage was based on the manufacturer’s recommendations and previous studies using this antagonist (22, 23). Vehicle control animals received Complan only. Mice were treated daily for 30 d after surgery, with treatment commencing 1 d after surgery. This treatment period was chosen because this is the time required to observe significant hypertrophic and fibrotic changes after infarction in this model and reflects long-term remodeling rather than the immediate response to injury.

At the end of the 30-d treatment period mean arterial pressure (MAP) was measured on the conscious mice by a noninvasive computerized tail cuff system (ADInstruments, Dunedin, New Zealand) as previously described (24). The mice were weighed and then euthanized with an anesthetic overdose (Halothane) before cervical dislocation. Cardiac puncture was performed to obtain a blood sample and hearts were photographed to measure infarct size. The hearts were rapidly excised, and the atria dissected from the ventricles, weighed, and immediately snap frozen in liquid nitrogen for RNA isolation (n = 6 per group), and the remaining hearts were fixed in formalin for histology (n = 2). Mice were weighed before being killed to allow heart weight to body weight ratios to be calculated. Whole left kidney (n = 6/group) was also snap frozen for RNA isolation.

RNA isolation
For each sample, total ventricular and kidney RNA was isolated by automated grinding in a Retsch MM301 tissue mill at 30 Hz for 10 min in 800 µl prechilled TRIzol (Invitrogen, Carlsbad, CA). Chloroform (160 µl) was added and samples were centrifuged at 12,000 x g for 15 min at room temperature. The RNA-containing supernatant was purified by RNeasy midicolumns according to the manufacturer’s instructions (QIAGEN, Hilden, Germany).

Quantitative real-time PCR analysis
Quantitative real-time PCR analysis was performed on selected genes [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), TGF-β1, TAK-1, collagen 1, β-myosin heavy chain, {alpha}-myosin heavy chain, angiotensinogen, ACE, and AT1R]. The cDNA was generated from 2.5 µg of ventricular and kidney total RNA as previously described (24).

Oligonucleotide primer sequences and PCR annealing temperatures for each gene studied are given in Table 1Go. PCRs were performed in a total volume of 30 µl containing 1 µl cDNA, 0.4 mM primers, 1x PCR buffer, 0.2 mM deoxynucleotide triphosphates, 1.5 mM MgCl2, 10 nM Sybr Green 1 (Roche, Indianapolis, IN), and 1 U TAQ-Ti DNA polymerase (Fisher Biotec, West Perth, Australia). The PCR conditions were optimized for each gene of interest, and the sequences of PCR products were confirmed by sequencing on an ABI 3100-Avant genetic analyzer (Applied Biosystems, Foster City, CA) before RT-PCR analysis. Levels of mRNA expression were evaluated by quantitative RT-PCR in a Rotor-Gene RG-3000 real-time PCR machine (Corbett Research, Sydney, Australia) as previously described (24). For each assay a hot start at 96 C for 2 min was performed before the following PCR cycling parameters: denaturation at 94 C for 30 sec, annealing for 35 sec at the gene-specific annealing temperature (Table 1Go), and extension at 72 C for 30 sec. Each sample underwent 30 cycles, after which a melt curve was performed. Each sample was assayed in duplicate and gene expression levels were quantified against a standard curve and expressed as picograms of message per microgram of total RNA (picograms per microgram of total RNA).


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  		TABLE 1. Primer sequences and annealing temperatures for RT-PCR assays

 
Histology
Hearts from each group were rapidly excised, fixed in 10% formalin, and paraffin embedded. Masson Trichrome staining was performed on 7-µm-thick heart sections to detect collagen deposition indicative of cardiac fibrosis.

Plasma renin activity (PRA)
Blood samples were taken when the animals were killed by cardiac puncture into EDTA tubes, centrifuged at 4 C, and stored at –80 C before assay for PRA as previously described (25).

Statistical analysis
Univariate analyses relating drug treatment and/or MI to indices of cardiac remodeling, blood pressure, and levels of ventricle and kidney gene expression were performed using ANOVA. Results are expressed as means and SEM. Bivariate relationships between expression levels for all genes were tested with Pearson’s correlation. All statistical analyses were performed using SPSS version 11 (SPSS Inc., Chicago, IL). P < 0.05 was taken to indicate statistical significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Cardiac hypertrophy
All animals survived the 30-d experimental period, and there was no significant difference in infarct size between groups. Overall, heart weight to body weight ratios (HW/BW) of mice treated with SD-208 were significantly decreased (P < 0.05) compared with animals receiving the vehicle control (Fig. 1AGo). This decrease in heart size occurred despite a significant elevation in β-myosin heavy chain gene expression (P < 0.05) compared with the {alpha}-myosin heavy chain in animals after infarct (Fig. 1BGo).


Figure 1
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  		FIG. 1. HW/BW ratios (A) and β-myosin heavy chain (MHC) to {alpha}-MHC gene expression ratios (B) in surgical sham and MI groups treated with control vehicle or SD-208. {dagger}, P < 0.05, overall significant effect between SD-208-treated groups compared with vehicle-treated groups; #, P < 0.05, overall significant effect between infarction groups compared with sham surgery groups.

 
Effect of TGF-β blockade on cardiac gene expression
There was no significant difference in TGF-β1 gene expression between groups (Fig. 2AGo); however, there was a trend for reduced TAK-1 gene expression in groups receiving SD-208 treatment (P = 0.06) when compared with vehicle-treated groups (Fig. 2BGo). Collagen 1 gene expression was significantly increased by myocardial infarction (P < 0.05). However, SD-208 treatment after infarction significantly reduced collagen 1 gene expression to noninfarct levels (P = 0.01, Fig. 2CGo) as well as reducing collagen protein expression in the noninfarcted left ventricle free wall (Fig. 3Go). There was no difference in collagen protein expression within the infarct itself between treatment groups. Furthermore, collagen 1 gene expression was positively correlated with TAK-1 expression (Pearson correlation coefficient = 0.658, P < 0.001).


Figure 2
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  		FIG. 2. Ventricular levels of TGF-β1 (A), TAK-1 (B), and collagen 1 (C) mRNA in surgical sham and MI groups treated with control vehicle or SD-208. Quantitated gene levels are expressed as picogram of message per microgram of total RNA (picogram per microgram of total RNA). {dagger}, P < 0.05, significant difference when compared with sham vehicle group; *, P < 0.05, significant difference when compared with infarct vehicle group.

 

Figure 3
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  		FIG. 3. Masson Trichrome staining of representative sections of noninfarcted left ventricle free wall from either an infarction animal treated with control vehicle (A) or an infarction animal treated with SD-208 (B). Blue staining indicates collagen deposition. Marked collagen deposition was observed in infarction animals treated with the control vehicle, compared with infarction animals treated with SD-208. Scale bars, 50 µm.

 
Treatment with SD-208 after infarction resulted in a significant decrease in angiotensinogen and AT1R gene expression when compared with the infarct plus vehicle group (P < 0.05, Fig. 4Go, B and D). Furthermore, those animals treated with SD-208 had significantly reduced ACE gene expression compared with vehicle-treated groups (P < 0.001, Fig. 4CGo). In addition, ACE expression was positively correlated to TAK-1 expression (Pearson correlation coefficient = 0.449, P < 0.05). Gene expression of ANP and BNP were also investigated; however, no significant differences in the gene expression of these peptides was observed between groups (data not shown).


Figure 4
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  		FIG. 4. MAP (A) and ventricular levels of angiotensinogen (B), ACE (C), and AT1R (D) mRNA in surgical sham and myocardial infarction groups treated with control vehicle or SD-208. Quantitated gene levels are expressed as picogram of message per microgram of total RNA (picogram per microgram of total RNA). **, P < 0.01, significant difference when compared with respective vehicle-treated groups; *, P < 0.05, significant difference when compared with infarct vehicle group; #, P < 0.001, overall significant effect between SD-208 groups compared with vehicle-treated groups.

 
Effect of TGF-β blockade on renal gene expression and PRA
Renal expression of genes of interest was investigated to determine the systemic effect of SD-208 treatment after myocardial infarction.

There was no significant difference in renal TGF-β1 gene expression between groups (Table 2Go); however, there was a significant reduction in TAK-1 and kidney collagen 1 gene expression after MI in groups receiving SD-208 treatment (P < 0.05) when compared with vehicle-treated infarct animals (Table 2Go). Kidney angiotensinogen was significantly increased by MI (P < 0.05); however, with SD-208 treatment after infarction angiotensinogen gene expression was significantly reduced (P < 0.05) to noninfarct levels (Table 2Go). There was a trend for reduced kidney ACE gene expression in groups receiving SD-208 treatment when compared with vehicle-treated groups and a significant reduction in kidney AT1R gene expression after myocardial infarction was observed in groups receiving SD-208 treatment (P < 0.05) when compared with vehicle-treated infarct animals (Table 2Go). In addition, kidney AT1R and kidney ACE expression were positively correlated to kidney TAK-1 expression (Pearson correlation coefficient = 0.606; P < 0.01 and 0.808; P < 0.01, respectively). The PRA was significantly increased by myocardial infarction (P < 0.05); however, with SD-208 treatment after infarction, PRA was significantly reduced (P < 0.05) to noninfarct levels (Table 2Go).


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  		TABLE 2. Kidney levels of TGF-β1, TAK-1, collagen 1, angiotensinogen, ACE, AT1R mRNA, and PRA in surgical sham and MI treated with control vehicle or SD-208

 
Blood pressure
SD-208 treatment had a hypotensive effect significantly reducing MAP in both sham and MI groups (P < 0.01, Fig. 4AGo), possibly as a result of the observed down-regulation of RAS gene expression and PRA.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the current study, blockade of TGF-β activity after MI reduced blood pressure, indices of cardiac remodeling and gene expression of components of the RAS. This is the first study to examine the cardiac and renal effects of the orally active TGF-β receptor 1 inhibitor, SD-208, in a model of MI.

TGF-β activity has been linked to a broad spectrum of biological actions including cellular growth, proliferation, and differentiation (26). Understanding the role of TGF-β in cardiac injury is complex due to the diverse effects elicited by this cytokine. TGF-β has an important role in the inflammatory and fibrotic response necessary for postinfarction repair of the heart; however, it is also a key mediator of the pathological fibrotic and hypertrophic remodeling, which occurs after infarction (27). In the present study, inhibition of TGF-β signaling significantly reduced cardiac mass and ventricular collagen 1 gene and protein expression. The decrease in heart weight occurred despite higher levels of β-myosin heavy-chain expression in animals after infarction, suggesting that the reduction in cardiac mass may be attributable, at least in part, to the marked decrease in collagen 1 seen with SD-208 treatment and suggests β-myosin heavy-chain expression is not controlled through a TGF-β ALK5-mediated pathway. Because interstitial fibrosis contributes to both diastolic and systolic dysfunction (28) as well as the impairment of cardiac conduction systems (27), the inhibition of this fibrosis pathway achieved with SD-208 treatment in these mice after infarction is likely to be important in moderating the degree of cardiac remodeling and subsequent development of heart failure. Indeed, Okada et al. (29) recently reported that inhibition of circulating TGF-β1 signaling (through adenoviral mediated overexpression of the soluble TGF-β type II receptor) attenuated postinfarction cardiac fibrosis in conjunction with decreased ventricular chamber dilation and improved postinfarct contractile function and reduced mortality.

In our model of MI, no difference was observed in total ventricular TGF-β1 gene expression between groups 30 d after surgery. This is consistent with other studies that have shown TGF-β1 expression is regulated temporally after infarction, peaking immediately after MI with levels and then reducing over time (30). However, we found that TAK-1, a significant downstream modulator of TGF-β signaling, tended to be reduced in those groups receiving SD-208. This is presumed to be beneficial, given that overexpression of TAK-1 causes cardiac hypertrophy, fibrosis, activation of fetal gene expression, and severe myocardial dysfunction (31). Furthermore, the TGF-β/TAK-1-p38MAPK pathway is activated in spared myocytes after infarction and is speculated to play an important role in the development of hypertrophy in the remodeling myocardium. In this study, blockade of the TGF-β receptor I successfully reduced levels of TAK-1 expression for 30 d after infarction. As expected, we saw a significant correlation between the decrease in cardiac TAK-1 and collagen 1, indicating that SD-208 was successful in blocking TGF-β and its downstream actions.

Extensive evidence suggests a direct functional association between the RAS and the TGF-β pathway (19). TGF-β expression is regulated by locally generated Ang II via AT1R binding in the infarcted heart, and ACE inhibitor and AT1R blocker treatment have been shown to markedly reduce levels of TGF-β1 in both hypertrophic and infarcted heart (32, 33). One of the most notable findings of the present study is that blocking TGF-β signaling resulted in a down-regulation in the expression of angiotensinogen, ACE, and AT1R as well as PRA. To date, other studies have indicated that TGF-β acts downstream of Ang II and is responsible for promoting myocyte growth and fibrosis in the heart (19). This is the first in vivo study to report that blockade of TGF-β signaling can modulate the expression of the RAS within the heart and kidney. Recently an in vitro study has shown that TGF-β1 stimulates AT1R gene expression through cross talk between the Smad and specific kinase signaling pathways that are simultaneously activated by ALK5 (34) and suggests the existence of a self-potentiating loop between the TGF-β and RAS systems. The observed down-regulation of the RAS in our study may therefore be attributed to the blockade of ALK5 activity with the antagonist SD-208.

The systemic gene suppression of the RAS in both the heart and kidney in sham and infarct animals treated with SD-208 and the decrease in PRA in infarct animals may have contributed to the fall in MAP and decrease in cardiac mass observed. A drop in MAP such as this would be considered beneficial after infarction, given the resulting reduction in workload for the failing heart. A reduction in blood pressure by inhibiting TGF-β signaling using specific neutralizing antibodies has been previously reported (35, 36, 37) and suggest that the antihypertensive effects may be due to the blockade of TGF-β actions on paracrine factors such as nitric oxide synthase, cyclooxygenase-2, and the RAS that regulate vascular tone (35), as well as imparting renal protection (37). This effect may have contributed to the decrease in blood pressure and HW/BW observed in the sham controls treated with SD-208 in this study. The deleterious remodeling effects of RAS activation post MI are well documented (27), and in this study we show a suppression of this system by TGF-β blockade with SD-208. Our finding of significant correlations between cardiac TAK-1 and ACE gene expression and kidney TAK-1 and kidney AT1R and ACE further reinforces the relationship between TGF-β signaling and the RAS.

Blockade of TGF-β may be of particular importance after MI, given the reports of up-regulation of TGF-β receptors in models of ischemia (1) as well as evidence suggesting that not only are higher levels of TGF-β1 produced after an ischemic myocardial event, but they also may also predispose to such an event (38). Recent studies indicate that the overexpression of TGF-β1 in vascular smooth muscle may lead to an increase in ECM production, contributing to the narrowing of arteries (38, 39), with the blockade of TGF-β signaling reversing this process (40). Taken together, these previous findings and those of the current study suggest that inhibition of TGF-β signaling pathways holds promise in ameliorating the deleterious effects of cardiac remodeling after infarction and in ischemic disease.

The results presented in the current study indicate that SD-208 is a hypotensive drug and that inhibition of the TGF-β receptor I after MI reduces indices of ventricular remodeling and has a novel beneficial role in reducing levels of the RAS.


   Footnotes
 
This work was supported by the National Heart Foundation of New Zealand. The compound SD-208 was gifted from Scios Inc.

Disclosure Statement: L.J.E., N.J.A.S., A.P.P., P.G.B., T.G.Y., A.M.R., and V.A.C. have nothing to declare. S.M. and A.P.P. were previously employed by Scios Inc.

First Published Online July 24, 2008

Abbreviations: ACE, Angiotensin-converting enzyme; ALK, activin receptor-like kinase; Ang II, angiotensin II; ANP, atrial natriuretic peptide; AT1R, Ang II type I receptor; BNP, brain natriuretic peptide; ECM, extracellular matrix; HW/BW, heart weight to body weight; MAP, mean arterial pressure; MI, myocardial infarction; RAS, renin-angiotensin system. Smad, phosphorylated mothers against decapentaplegic; TAK1, TGF-β-activated kinase-1.

Received February 5, 2008.

Accepted for publication July 14, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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