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Angiotensin-(1–7) inhibits growth of cardiac myocytes through activation of the mas receptor

Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 9 September 2004 ; accepted in final form 31 May 2005

	ABSTRACT

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Peptide hormones such as ANG II and endothelin contribute to cardiac remodeling after myocardial infarction by stimulating myocyte hypertrophy and myofibroblast proliferation. In contrast, angiotensin-(1–7) [ANG-(1–7)] infusion after myocardial infarction reduced myocyte size and attenuated ventricular dysfunction and remodeling. We measured the effect of ANG-(1–7) on protein and DNA synthesis in cultured neonatal rat myocytes to assess the role of the heptapeptide in cell growth. ANG-(1–7) significantly attenuated either fetal bovine serum- or endothelin-1-stimulated [³H]leucine incorporation into myocytes with no effect on [³H]thymidine incorporation. [D-Ala⁷]-ANG-(1–7), the selective ANG type 1–7 (AT_1–7) receptor antagonist, blocked the ANG-(1–7)-mediated reduction in protein synthesis in cardiac myocytes, whereas the AT₁ and AT₂ angiotensin peptide receptors were ineffective. Serum-stimulated ERK1/ERK2 mitogen-activated protein kinase activity was significantly decreased by ANG-(1–7) in myocytes, a response that was also blocked by [D-Ala⁷]-ANG-(1–7). Both rat heart and cardiac myocytes express the mRNA for the mas receptor, and a 59-kDa immunoreactive protein was identified in both extracts of rat heart and cultured myocytes by Western blot hybridization with the use of an antibody to mas, an ANG-(1–7) receptor. Transfection of cultured myocytes with an antisense oligonucleotide to the mas receptor blocked the ANG-(1–7)-mediated inhibition of serum-stimulated MAPK activation, whereas a sense oligonucleotide was ineffective. These results suggest that ANG-(1–7) reduces the growth of cardiomyocytes through activation of the mas receptor. Because ANG-(1–7) is elevated after treatment with angiotensin-converting enzyme inhibitors or AT₁ receptor blockers, ANG-(1–7) may contribute to their beneficial effects on cardiac dysfunction and ventricular remodeling after myocardial infarction.

cardiac hypertrophy; mitogen-activated protein kinases

Several recent studies also suggest that ANG-(1–7) participates in the regulation of cardiac function. Averill et al. (2) first reported the presence of intense ANG-(1–7) immunoreactivity within the myocytes in the rat heart as well as a significant increase in ANG-(1–7) immunoreactivity in the myocytes surrounding an ischemic zone. These findings correlate with studies showing the presence of ANG-(1–7) in the venous effluent collected from the canine coronary sinus (38) and the generation of ANG-(1–7) from ANG I and ANG II in the interstitial fluid collected from microdialysis probes placed in the canine left ventricle (52). Recent studies identified a novel enzyme that converts ANG II to ANG-(1–7), ACE2, which plays a critical role in cardiac function (12). We showed an upregulation of ACE2 mRNA by losartan treatment of rats after myocardial infarction (23). The increased ACE2 mRNA correlated with elevated plasma ANG-(1–7) and reversal of cardiac remodeling. In addition, Zisman et al. (54) showed that ANG-(1–7) is made in the intact human heart, and its production was suppressed by an ACE inhibitor, suggesting that a major pathway for the formation of ANG-(1–7) was directly dependent on the availability of ANG II as a substrate. Collectively, these results provide evidence of a role for ACE2 and ANG-(1–7) in the heart as well as in improved cardiac function after treatment with AT₁ receptor antagonists.

ANG-(1–7) is a poor competitor of the AT₁ or AT₂ angiotensin receptor (26, 27, 49), and the majority of responses to ANG-(1–7) are not blocked by AT₁ or AT₂ receptor antagonists (3, 6, 27, 35). However, many of these responses are inhibited by [D-Ala⁷]-ANG-(1–7), a modified form of ANG-(1–7) in which proline at position 7 is replaced by D-Ala (39, 48). [D-Ala⁷]-ANG-(1–7) selectively blocks responses to ANG-(1–7), is a poor competitor of the AT₁ or AT₂ receptor, and does not block pressor or contractile responses to ANG II (5, 16, 39). Santos et al. (40) recently identified the orphan G protein-coupled receptor mas as an ANG-(1–7) receptor. Chinese hamster ovary cells transfected with mas have a high-affinity binding site for ¹²⁵I-labeled ANG-(1–7), which is competed for by [D-Ala⁷]-ANG-(1–7), and vasodilatory and renal responses to ANG-(1–7) are attenuated in mas-depleted mice.

Loot et al. (30) reported that ANG-(1–7) infusion after coronary artery ligation was associated with the preservation of left ventricular function, reversal of cardiac remodeling, and reduction in myocyte size. These results suggest a role for ANG-(1–7) in both the regulation of cardiac dynamics and myocyte growth. We evaluated the effect of ANG-(1–7) on neonatal rat myocyte cell growth and investigated whether the mas receptor mediated this response to gain further insight into the cellular mechanisms responsible for the actions of ANG-(1–7) in cardiac function and remodeling.

	METHODS

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Materials. ANG-(1–7), endothelin-1 (ET-1), and [D-Ala⁷]-ANG-(1–7) were obtained from Bachem California (Torrance, CA). DMEM-F12, FBS, penicillin, streptomycin, and Oligofectamine were obtained from GIBCO Invitrogen (Gaithersburg, MD). Phospho-specific antibodies against ERK1/ERK2 were obtained from Cell Signaling (Cambridge, MA). Antisense and sense oligonucleotides to mas were synthesized by the Wake Forest University Cancer Center DNA Synthesis Core. All other reagents were purchased from Sigma Chemical (St. Louis, MO).

Isolation of neonatal rat cardiac myocytes. Neonatal rat cardiomyocytes were isolated from the ventricles of Sprague-Dawley rats by proteolytic digestion and differential plating, as previously described (1, 37). Myocytes were collected and maintained in DMEM-F12 containing 10% FBS, 10 µg/ml insulin, 10 µg/ml holo-transferrin, 100 µM bromodeoxyuridine (to prevent proliferation of nonmyocytes), and the antibiotics ampicillin and streptomycin. Before their use, myocytes were incubated for 48 h in the same media in the absence of serum and bromodeoxyuridine (serum-free media). Cells isolated by this protocol routinely showed positive immunoreactive staining for antisarcomeric myosin (1:100 dilutions, Sigma) and little immunoreactivity labeling with antibodies to -smooth muscle-specific actin, fibronectin, or vimentin (1:100 dilutions; Sigma). All experimental procedures were performed in accordance with guidelines set forth by the Institutional Animal Care and Use Committee.

Measurement of thymidine and leucine incorporation. Tritiated thymidine and leucine incorporation into cardiac myocytes was measured in cells in 24-well culture plates. Cells were treated for 48 h in the presence and absence of 1% FBS, 10 nM ET-1, and ANG receptor antagonists as indicated in individual experiments. One microcurie of either [³H]thymidine or [³H]leucine per milliliter of culture medium was added to each well. The incorporation of [³H]thymidine into newly synthesized DNA or [³H]leucine into newly synthesized protein was determined after precipitation of acid-insoluble material with ice-cold 10% trichloroacetic acid. The acid-insoluble material was dissolved in 0.25 N NaOH-0.1% sodium dodecyl sulfate and quantified by liquid scintillation spectrometry.

Measurement of ERK1/ERK2 activities and Western blot hybridization. Cells were incubated with 1% FBS for 10 min or preincubated with 100 nM ANG-(1–7) for 6 h followed by a 10-min treatment with 1% FBS. Cell lysates were prepared by washing the cells with PBS (50 mM NaHPO₄ and 0.15 mM NaCl, pH 7.2) containing 0.01 mM NaVO₄ to prevent the dephosphorylation of activated, phosphorylated proteins. Cellular protein was solubilized in lysis buffer (100 mmol/l NaCl, 50 mmol/l NaFl, and 5 mmol/l EDTA, 1% Triton X-100, and 50 mmol/l Tris·HCl, pH 7.4) containing 0.01 mmol/l NaVO₄, 0.1 mmol/l PMSF, and 0.6 µmol/l leupeptin for 30 min on ice. The supernatant was clarified by centrifugation (12,000 g for 10 min at 4°C), and the protein concentration was measured by the Lowry method (31).

For Western blot hybridization, solubilized proteins (20 µg/well) were separated on 10% polyacrylamide gels with the use of the buffer system of Laemmli and then transferred to polyvinylidene difluoride membranes (Amersham Pharmacia, Piscataway, NJ) by electrophoresis. Nonspecific binding to the membranes was blocked by incubation in 5% Blotto (5% evaporated milk; 0.1% Tween 20 in 50 mmol/l Tris·HCl, pH = 7.4; and 50 mmol/l NaCl). Membranes were subsequently probed with a specific antibody to the activated phosphorylated form of the ERK1/ERK2 MAPKs (1:1,000 dilution; Cell Signaling Technology, Beverly, MA) to measure the level of the phosphorylated ERK or with a specific antibody to mas (1:2,000 dilution) to identify the mas receptor, followed by incubation with goat anti-rabbit antibody (1:1,000 dilution) coupled to horseradish peroxidase. Actin (-actin; Abcam) immunostaining was used as a loading control. Immunoreactive bands were visualized with the use of enhanced chemiluminescence reagents and quantified by densitometry.

Immunocytochemistry. Myocytes were grown in eight-well chamber slides for immunocytochemical analysis. Cells were fixed in 4% paraformaldehyde in PBS and permeabilized with 0.1% Triton X-100 in PBS. Cells were incubated overnight at 4°C with mas antibody purified on a peptide-affinity column. Cells were subsequently incubated with an FITC-coupled goat anti-rabbit antibody (1:200 dilution) and visualized by fluorescence microscopy.

RNA isolation and RT real-time PCR. RNA was isolated from rat hearts or cultured neonatal myocytes with the use of the TRIzol reagent (GIBCO Invitrogen, Carlsbad, CA) as directed by the manufacturer. The RNA was incubated with RQ1 DNase (Promega, Madison, WI) to eliminate any residual DNA that would amplify during the PCR. The RNA concentration and integrity were assessed with an Agilent 2100 Bioanalyzer with an RNA 6000 Nano LabChip (Agilent Technologies, Palo Alto, CA). Approximately 1 µg of total RNA was reverse transcribed with the use of avian myeloblastosis virus RT in a 20-µl reaction mixture containing deoxyribonucleotides, random hexamers, and RNase inhibitor in RT buffer. The RT reaction product was heated at 95°C to terminate the reaction. For real-time PCR, 2 µl of the resultant cDNA were added to TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA) with the mas-specific primer/probe set, and amplification was performed on an ABI 7000 Sequence Detection System. The primer/probe set consisted of forward primer 5'-TTCATAGCCATCCTCAGCTTCTTG-3', reverse primer 5'-GTTCTTCCGTATCTTCACCACCAA-3', and probe 5'-FAM-TTCACTCCGCTCATGTTAG-NFQ-3'. The mixtures were heated at 50°C for 2 min and at 95°C for 10 min followed by 40 cycles at 95°C for 15 s and 60°C for 1 min. All reactions were performed in triplicate, and 18S ribosomal RNA, amplified with the use of the TaqMan Ribosomal RNA control kit (Applied Biosystems), served as an internal control. The results were quantified as C_t values, where C_t is defined as the threshold cycle of PCR at which the amplified product is first detected and the values are expressed as the ratio of target to control.

Transfection of myocytes with antisense oligonucleotides. Myocytes were transfected with mas sense and antisense oligonucleotides for 4 h at 37°C with the use of Oligofectamine according to the manufacturer's directions. The sense oligonucleotide was 5'-ATGGACCAATCAAATATGAC-3', and the antisense oligonucleotide was 5'-GTCATATTTGATTGGTCCAT-3'. Cells were incubated before their use for an additional 48 h in OptiMem containing 10% FBS. Transfected cells were treated with 1 µmol/l ANG-(1–7) for 6 h and stimulated with 1% FBS for 10 min. ERK1/ERK2 activity was determined with the use of a phospho-specific antibody as described in Measurement of ERK1/ERK2 activities and Western blot hybridization.

Statistics. All data are presented as means ± SE. Statistical differences were evaluated by ANOVA followed by Dunnett's post hoc test. The criterion for statistical significance was set at P < 0.05.

	RESULTS

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Inhibition of cardiomyocyte cell growth by ANG-(1–7). Cardiac myocytes were isolated from neonatal rat hearts to test the hypothesis that ANG-(1–7) regulates the growth of cardiac cells. Myocytes were incubated in media depleted of serum for 48 h and then treated with 1% FBS or 10 nM ET-1 in the presence and absence of ANG-(1–7). Either [³H]thymidine, to measure incorporation into DNA as an indicator of DNA synthesis, or [³H]leucine, as an indicator of protein synthesis, was added to separate myocyte cultures. ANG-(1–7) had no effect on [³H]thymidine incorporation into cardiac myocytes. Both FBS and ET-1 stimulated [³H]leucine incorporation into protein; FBS increased [³H]leucine incorporation by 186.1 ± 37.1% above control (n = cells isolated from 5 litters of neonatal rat pups, in triplicate), and ET-1 caused a 48.6 ± 17.2% increase above control (n = cells isolated from 3 litters of neonatal rat pups, in triplicate). Treatment with ANG-(1–7) caused a significant reduction in both serum- and ET-1-stimulated [³H]leucine incorporation into cardiomyocytes, as shown in Fig. 1. Figure 2 shows that [D-Ala⁷]-ANG-(1–7), the selective AT_1–7 receptor antagonist, blocked the inhibitory effects of ANG-(1–7) in serum-stimulated cardiac myocytes. In contrast, blockade of AT₁ and AT₂ receptors with losartan and PD-123319, respectively, had no effect on the inhibitory actions of ANG-(1–7) on cardiac protein synthesis. These results suggest that ANG-(1–7) inhibits protein synthesis in cardiomyocytes with no effect on DNA production through activation of a [D-Ala⁷]-ANG-(1–7)-sensitive receptor.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Effect of angiotensin-(1–7) [ANG-(1–7)] on leucine incorporation in myocytes. Myocytes in serum-free media were incubated for 48 h with 1% FBS or 10 nM endothelin-1 (ET-1) in presence of ANG-(1–7). [3H]leucine incorporation into acid-insoluble protein was used as a measure of protein synthesis. Data are percent mitogen-stimulated [3H]leucine incorporation (either 1% FBS or 10 nM ET-1) in absence of ANG-(1–7); n = cells isolated from 3 to 5 litters of neonatal rat pups, in triplicate. *P < 0.05 compared with either FBS or ET-1 in absence of ANG-(1–7).

View larger version (13K): [in this window] [in a new window]   Fig. 2. Effect of receptor antagonists on ANG-(1–7)-inhibition of leucine incorporation in myocytes. Myocytes in serum-free media were incubated for 48 h with 1% FBS or 1% FBS and 100 nM ANG-(1–7) (A7) in presence or absence of 1 µmol/l [D-Ala7]-ANG-(1–7) (Dala), 1 µmol/l losartan (Los), or 1 µmol/l PD-123319 (PD). Data are percent FBS-stimulated [3H]leucine incorporation in absence of ANG-(1–7). Receptor antagonists alone (Dala, Los, or PD) had no effect on FBS-stimulated [3H]leucine incorporation; n = cells isolated from 4 litters of neonatal rat pups, in triplicate. *P < 0.05 compared with FBS alone.

View larger version (27K): [in this window] [in a new window]   Fig. 3. Effect of ANG-(1–7) on ERK1/ERK2 activities. Myocytes in serum-free media were pretreated for 6 h with either 100 nmol/l ANG-(1–7) or 100 nmol/l ANG-(1–7) and 1 µmol/l Dala in presence of 1 µmol/l Los. FBS (1%) was added, and incubation was continued for an additional 10 min. ERK1/ERK2 activities were determined with the use of a phospho-specific antibody as described in Measurement of ERK1/ERK2 activities and Western blot hybridization. A: representative blot analysis showing 1% FBS-stimulated phospho-ERK1/ERK2 and actin immunoreactivity in presence or absence of ANG-(1–7). B: data are percent control in presence of 1% FBS; n = cells isolated from 2 to 4 litters of neonatal rat pups, in duplicate or triplicate. *P < 0.05 compared with FBS treatment alone.

View larger version (25K): [in this window] [in a new window]   Fig. 4. Identification of mas mRNA and protein in rat heart and neonatal cardiac myocytes. A: mas mRNA isolated from rat heart (n = 4 rats) or cultured myocytes (n = cells isolated from 4 litters of neonatal rat pups) was compared by RT real-time PCR as described in METHODS. B: the 59-kDa immunoreactive protein was visualized by Western blot hybridization in rat heart and cultured myocytes with use of a peptide antibody to mas.

View larger version (76K): [in this window] [in a new window]   Fig. 5. Immunocytochemical localization of mas receptor in neonatal rat myocytes. Left: mas receptor localized in myocytes isolated from neonatal rat heart with use of a mas antibody that was affinity purified on a peptide affinity column. Right: myocytes incubated with antibody preabsorbed with 10 µmol/l of peptide used to generate antibody.

View larger version (22K): [in this window] [in a new window]   Fig. 6. Inhibition of ANG-(1–7)-mediated MAPK activity by mas receptor antisense oligonucleotides. Semiconfluent monolayers of myocytes were transfected with either mas sense or antisense oligonucleotides with use of Oligofectamine as described in METHODS. After 48 h, transfected cells were incubated for an additional 6 h with or without 100 nmol/l ANG-(1–7) and 1 µmol/l Los. Cells were treated with 1% FBS for 10 min, and ERK1/ERK2 activity was measured with use of a phospho-specific antibody as described in Measurement of ERK1/ERK2 activities and Western blot hybridization. A: representative blot analyses showing 1% FBS-stimulated phospho-ERK1/ERK2 and actin immunoreactivity in presence or absence of ANG-(1–7) after transfection with either sense oligonucleotide to mas or antisense oligonucleotide to mas. B: data are percent control in presence of 1% FBS; n = cells isolated from 3 to 7 litters of neonatal rat pups, in duplicate or triplicate. *P < 0.05 compared with activity in presence of sense oligonucleotide.

	DISCUSSION

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ANG-(1–7) also caused a significant reduction in serum-stimulated ERK1/ERK2 activities. Tallant and Clark (47) previously showed that ANG-(1–7) inhibits ANG II or PDGF stimulation of ERK1 and ERK2 in vascular smooth muscle cells (VSMCs). Furthermore, Tallant and Gallagher (50) recently reported that the ANG-(1–7)-mediated inhibition of MAPK signaling in VSMCs was prevented by pretreatment with either a serine/threonine or tyrosine phosphatase inhibitor, suggesting that ANG-(1–7) upregulates a protein phosphatase(s) to inhibit ERK1/ERK2 activities. ANG-(1–7) may reduce ERK1/ERK2 activity in cardiac myocytes by stimulating or inducing the expression of an MAPK phosphatase. Transfection of MAPK phosphatase-1 into neonatal cardiac myocytes inhibited the expression of atrial natriuretic factor, ventricular myosin light chain 2, and -myosin heavy chain in response to the hypertrophic agonists phenylephrine or ET-1 (18). In addition, constitutive expression of MAPK phosphatase-1 in cultured myocytes with the use of adenovirus-mediated gene transfer blocked the activation of ERK1/ERK2 and prevented agonist-induced hypertrophy (7). Alternatively, ANG-(1–7) could inhibit MAPK activity in cardiomyocytes by a reduction in MAPK-ERK1/2 (MEK1/2) activity.

The MAPKs ERK1 and ERK2 are activated by hypertrophic agonists in cultured cardiac myocytes (1, 9, 43). The transfection of constitutively active MEK1 augmented atrial natriuretic factor promoter activity in cultured myocytes, whereas a dominant-negative MEK1 construct attenuated its activity (20). Furthermore, the MEK1 inhibitor PD-98059 reduced agonist-induced natriuretic promoter activity in cardiac cells (29). Transgenic mice containing an activated MEK1 cDNA exhibited a phenotype of compensated cardiac hypertrophy (8). This is consistent with the hypertrophic response observed in cardiomyocytes infected with an activated MEK1-encoding adenovirus (8, 51). Glennon et al. (21) used antisense oligonucleotides to reduce p42 and p44 (ERK2 and ERK1) by 44% and 60% in cardiac myocytes; this resulted in significant reductions in cardiac myocyte morphology and gene expression that did not require total depletion of MAPK. Collectively, these results provide strong evidence that activation of the MEK/ERK1/ERK2 pathway plays a critical role in myocyte growth. Because ANG-(1–7) reduced mitogen-stimulated ERK1/ERK2 activities in cultured myocytes, our results are consistent with a role for the heptapeptide in regulating myocyte growth.

Both the ANG-(1–7)-mediated reduction in [³H]leucine incorporation and the ERK1/ERK2 signaling were blocked by the ANG-(1–7)-selective receptor antagonist [D-Ala⁷]-ANG-(1–7). These results suggest that the antigrowth response to ANG-(1–7) is mediated by an AT_1–7 receptor. Santos et al. (40) demonstrated that the orphan G protein-coupled receptor mas is an ANG-(1–7) receptor. We recently reported that antisense oligonucleotides and small interfering RNAs to mas blocked the antiproliferative response to ANG-(1–7) in VSMCs (46). We showed that mas mRNA and protein are present in the rat heart as well as in cardiac myocytes isolated from the neonatal rat heart. The antibody to mas labeled a 59-kDa protein, suggesting the presence of a glycosylated form of the mas receptor in the rat heart and cultured cardiac myocytes. Furthermore, we show that an antisense oligonucleotide to the mas receptor blocks the stimulation of cardiomyocyte serum-stimulated ERK1/ERK2 activities. This same antisense oligonucleotide also prevented the ANG-(1–7)-mediated inhibition of MAPK activity in VSMCs and reduced mas immunoreactivity to 69.9 ± 8.8% (unpublished observation). These results suggest that mas mediates the antigrowth response to ANG-(1–7) in cardiac myocytes.

Several lines of evidence suggest that ANG II plays a critical role in mediating cardiac hypertrophy through direct effects on contractility, induction of growth-promoting genes, increased protein synthesis, and cell growth (41). In the mature heart, ANG II causes cardiac hypertrophy independent of its effect on blood pressure, whereas blockade of the renin-angiotensin system attenuates or reverses the molecular and cellular adaptations to pressure overload (13, 36). In contrast, ANG-(1–7) attenuates the development of heart failure postmyocardial infarction (30) as well as acts as an antiarrhythmogenic factor during myocardial ischemia-reperfusion (38). Because ANG-(1–7) reduces the agonist-mediated increase in protein synthesis and MAPK signaling in cultured myocytes and because plasma ANG-(1–7) levels are increased after treatment with ACE inhibitors or AT₁ receptor blockers (10, 28, 32), ANG-(1–7) may participate in the improvement in cardiac function.

In conclusion, we showed that ANG-(1–7) inhibits protein synthesis in cardiac myocytes through activation of the cardiac mas receptor and inhibition of the MAPK pathway. ANG-(1–7) immunoreactivity is present in the heart (2) along with a novel enzyme that generates ANG-(1–7) from ANG II, ACE2 (14, 53, 54). Because we showed an increase in ACE2 mRNA and ANG-(1–7) in the heart after blockade of AT₁ receptors that correlates with improved cardiac function after coronary artery ligation (2, 23), our results suggest that ANG-(1–7) may contribute to the beneficial effects of AT₁ receptor blockers on cardiac dysfunction and ventricular remodeling after myocardial infarction.

	GRANTS

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This work was supported by National Heart, Lung, and Blood Institute Grant HL-51952. In addition, we gratefully acknowledge grant support in part provided by Unifi, Greensboro, NC, and Farley-Hudson Foundation, Jacksonville, NC. Losartan was a kind gift of Merck.

	ACKNOWLEDGMENTS

 
We acknowledge the technical assistance of L. Tenille Howard, R. Lanning, and B. Bernish.

	FOOTNOTES

 

Address for reprint requests and other correspondence: E. Ann Tallant, Hypertension and Vascular Disease Center, Wake Forest Univ. School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1032 (e-mail: atallant{at}wfubmc.edu)

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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