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(Hypertension. 2002;39:803.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Posttranscriptional Control of BNP Gene Expression in Angiotensin II–Induced Hypertension

Maria Suo; Nina Hautala; Gábor Földes; István Szokodi; Miklós Tóth; Hanna Leskinen; Paavo Uusimaa; Olli Vuolteenaho; Mona Nemer; Heikki Ruskoaho

From the Department of Pharmacology and Toxicology (M.S., N.H., I.S., H.L., H.R.), Department of Physiology (O.V.), Department of Internal Medicine (P.U.), Biocenter Oulu, University of Oulu, Oulu, Finland; First Department of Medicine, Semmelweis Medical University (G.F., M.T.), Budapest, Hungary; and Clinical Research Institute of Montreal, University of Montreal (M.N.), Montreal, Canada.

Correspondence to Heikki Ruskoaho, MD, PhD, Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 University of Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi

	Abstract

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B-type natriuretic peptide (BNP) plasma concentrations are raised in patients with heart failure. In several experimental models of cardiac overload, however, BNP mRNA and plasma BNP peptide levels are normal, despite the persistent increase in blood pressure and ventricular hypertrophy. In this study, the role of transcriptional mechanisms in the regulation of BNP gene expression were studied in angiotensin (Ang) II–induced hypertension by injecting DNA constructs containing the BNP promoter (-2200 to 75 bp of the transcriptional start site) linked to luciferase reporter into rat myocardium. Ang II was administered to conscious rats via intravenous infusion for 2 hours or by subcutaneous minipumps for 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. Ang II increased blood pressure and cardiac mass and induced changes in diastolic function. The left ventricular BNP mRNA levels increased 2.2-fold (P<0.001) at 2 hours and peaked at 12 hours (5.2-fold, P<0.001). Thereafter, BNP mRNA levels decreased (1.8-fold induction at 3 days, P<0.05) and returned to control levels at 1 week, despite persistent hypertension and myocardial hypertrophy. Left ventricular BNP peptide concentrations followed the changes in BNP mRNA levels. The BNP promoter was activated 2.7-fold (P<0.05) at 2 hours and remained upregulated up to 2 weeks (2.8-fold, P<0.05) during Ang II infusion, except at 12 hours. These results indicate that posttranscriptional control plays a major role in the regulation of ventricular BNP gene expression in Ang II–induced hypertension.

Key Words: angiotensin II • blood pressure • gene expression • transcription • hypertrophy • natriuretic peptides

	Introduction

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B-type natriuretic peptide (BNP) is a cardiac hormone that regulates blood pressure and fluid homeostasis.^1,2 The plasma concentration of BNP is raised in patients with cardiac disease, particularly those with heart failure.^3,4 BNP level is useful in the diagnosis of congestive heart failure⁵ and may effectively guide treatment of patients in heart failure.^6,7 In experimental animal models, cardiac BNP gene expression increases rapidly in response to hemodynamic overload.^8–10 However, controversy persists regarding to BNP gene expression in ventricular myocardium under normal conditions and in chronic cardiac overload. Indeed, conflicting studies both in the human and in animals describe either increased^9,11–14 or unchanged left ventricular BNP mRNA levels^15–20 in heart failure and hypertension. The reason for the normal BNP mRNA levels despite constant cardiac overload is not known but could result from transcriptional and/or translational mechanisms. To date, there are no reports on the molecular mechanisms responsible for regulating the BNP gene expression during cardiac overload in vivo.

The aim of this study was to examine the effect of pressure overload on BNP gene expression and transcription in vivo. Hemodynamics, cardiac hypertrophy, systolic and diastolic function, left ventricular BNP mRNA and immunoreactive (ir)-BNP levels, and plasma ir-BNP concentrations were measured in rats infused with angiotensin (Ang) II for 2 hours, 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. To measure the level of BNP gene transcription, DNA constructs containing the rat BNP promoter 2200 bp upstream of the transcription initiation site linked to a reporter gene²¹ were injected into the left ventricular myocardium of rats. Finally, to explore further the possible mechanisms regulating BNP mRNA levels, we measured BNP activator protein-1 (AP-1) DNA binding activities in the left ventricle of vehicle- and Ang II–treated rats.

	Methods

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Plasmids and In Vivo Myocardial Gene Transfer
Rat BNP-luciferase plasmids containing BNP promoter fragment were obtained by cloning a HindIII-SstI fragment encompassing nucleotides -2200 to 75 relative to the transcriptional start site of rat BNP gene into pXP-2 vector.²² Male 2-month-old Sprague-Dawley rats (270 to 300 g, obtained from the Center for Experimental Animals, Oulu, Finland) were anesthetized with 250 µg/kg medetomidine hydrochloride and 50 mg/kg ketamine hydrochloride IP, and 100 µL of plasmids in 0.9% NaCl was injected directly into the left ventricular free wall close to the apex.^21,23 Plasmid DNA consisted of 10 µg of the reporter construct and 100 µg of a ß-galactosidase expression vector (pSVß-gal, Promega Co) to correct for variation in transfection efficiency. Left ventricular reporter gene expressions were assayed as previously described.²¹ The experimental design was approved by the Animal Use and Care Committee of the University of Oulu.

Induction of Pressure Overload and Tissue Preparation
Ang II was administered to conscious rats via intravenous infusion for 2 hours or by subcutaneous osmotic minipumps (B & K Universal AB) for 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. On the sixth day after DNA injection, the rats were instrumented under anesthesia for the measurements of hemodynamics and infusions.⁹ Then, on the seventh day after the injection, Ang II (30 µg · kg^-1 · h^-1) or 0.9% NaCl was infused intravenously for 2 hours, and the rats were decapitated. For the 6-hour, 12-hour, and 3-day experiments, the minipumps for Ang II (33.3 µg · kg^-1 · h^-1) or 0.9% NaCl infusion were installed under anesthesia 6 hours, 12 hours, and 3 days before the decapitation and 1 week after the plasmid injections. For the 1-week and 2-week experiments, minipumps were installed at the time of the plasmid DNA injection. Left ventricles were prepared for the mRNA and peptide determinations and gel shift assays at the end of Ang II and vehicle infusions.²⁴

Blood Pressure Monitoring
The hemodynamics in conscious, freely moving animals in the 2-hour experiment were measured as described previously.²⁵ For telemetric monitoring of blood pressure in minipump experiments, rats were instrumented with a catheter in the descending aorta coupled with a sensor and transmitter (TA11PA-C40; Data Sciences).²¹ Ang II or 0.9% NaCl infusion with osmotic minipumps was started 7 days after surgery.

Echocardiography
Left ventricular function and chamber dimensions were assessed by transthoracic echocardiography using Acuson Ultrasound System (Sequoia 512) and a 15-MHz linear transducer (15L8). Under ketamine (50 mg/kg IP) and xylazine (10 mg/kg IP) anesthesia using 2D imaging, a short-axis view of the left ventricle at the level of the papillary muscles was obtained for the M-mode recording. Left ventricular end-systolic (LVESD) and end-diastolic (LVEDD) dimensions as well as thickness of interventricular septum (IVS) and posterior wall (PW) were measured from the M-mode tracings. LV fractional shortening (LVFS) and ejection fraction (EF) were calculated from the M-mode LV dimensions using the following formulas: LVFS (%)=[(LVEDD-LVESD)/LVEDD]x100 and EF(%)=[(LVEDD³-LVESD³)/LVEDD³]x100. Mitral flow was recorded from an apical 4-chamber view. Measurements of peak flow velocity of the early rapid diastolic filling wave (E) and peak flow velocity of the late diastolic filling wave (A) were made, and the E/A ratio was calculated.

Gel Mobility Shift Assays
Gel mobility shift assays from the left ventricles were prepared as previously described.²⁴ The specificity of AP-1 binding was confirmed by competition and supershift analysis.

Isolation and Analysis of Cytoplasmic RNA and BNP Radioimmunoassay
Isolation of RNA, Northern blot analysis, and BNP radioimmunoassay were performed as previously described.^9,24,25

Statistical Analysis
Results are expressed as mean±SEM. Student’s t test was used for comparison between 2 groups. The hemodynamic variables were analyzed with 2-way repeated-measures ANOVA. Echocardiographic measurements were analyzed using normalized values with 1-way ANOVA followed by Student-Newman-Keuls post hoc test. A value of P<0.05 was considered statistically significant.

	Results

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Ang II–Induced Hypertension and Myocardial Hypertrophy
In conscious rats, intravenous infusion of Ang II for 2 hours raised mean arterial pressure from 123±10 to 163±9 mm Hg (n=18, P<0.001), associated with a significant decrease in heart rate (data not shown). Both mean arterial pressure (119±13 versus 117±12 mm Hg, n=14) and heart rate (data not shown) remained unchanged in the vehicle-infused rats. When administered by subcutaneous minipumps, Ang II increased mean arterial pressure within 3 hours, which persisted throughout the 2 weeks of infusion (Figure 1A). Initially, heart rate decreased in response to Ang II infusion; later it remained elevated in Ang II–infused rats compared with controls (Figure 1B). The index of ventricular hypertrophy, the ventricular weight–to–body weight ratio, was significantly increased at 12 hours and onward in Ang II–treated rats (Table 1).

View larger version (17K): [in this window] [in a new window]   Figure 1. A, Mean arterial pressure (MAP) in conscious rats during Ang II infusion by subcutaneous minipumps for 2 weeks. P<0.05 after 3 hours and P<0.001 after 1 day of the infusion. B, Heart rate (HR) was lower at the first day (P<0.05) and increased at 6 days (P<0.05) during the Ang II infusion. Values are mean±SEM. Vehicle (n=10, ), Ang II (n=10, •). Ang II vs vehicle, repeated-measures ANOVA.

View this table: [in this window] [in a new window]   Table 1. Effects of Ang II Infusion on Body and Ventricular Weights and Left Ventricular and Plasma ir-BNP Concentrations

Echocardiographic Measurements
The thickness of the interventricular septum (F=26.0, P<0.001) and left ventricular posterior wall (F=22.0, P<0.002) was increased during Ang II infusion at 1 and 2 weeks (Table 2). Left ventricular ejection fraction and fractional shortening were not different in vehicle- and Ang II–infused rats at any time point. However, the E/A ratio was significantly lower in Ang II–infused rats compared with control rats (F=28.5, P<0.001), suggesting changes in diastolic function (Table 2).

View this table: [in this window] [in a new window]   Table 2. Echocardiographic Measurements in Ang II–Infused Rats

Ventricular BNP Gene Expression During Ang II Infusion
In Ang II–treated rats, left ventricular BNP mRNA levels increased 2.2-fold (P<0.001) by 2 hours and peaked at 12 hours (5.2-fold, P<0.001) (Figure 2A). Thereafter, BNP mRNA levels decreased (at 3 days, 1.8-fold, P<0.05) and returned to control levels at 1 week. Left ventricular ir-BNP peptide levels peaked at 6 hours (3.8-fold, vehicle versus Ang II) and reduced gradually to the control levels (at 2 weeks, vehicle versus Ang II) (Table 1). During Ang II infusion, plasma ir-BNP levels were highest at 12 hours (3.3-fold, vehicle versus Ang II) and remained elevated up to 2 weeks (1.4-fold) (Table 1). Of note, baseline plasma ir-BNP levels were highest in both vehicle- and Ang II–infused rats at 2 hours (Table 1), probably because instrumentation of rats under anesthesia was performed 1 day before hemodynamic measurements and infusions.

View larger version (18K): [in this window] [in a new window]   Figure 2. A, Left ventricular BNP mRNA levels, expressed as the ratio of BNP mRNA to 18S. 2h indicates 2 hours (n=8 and 8); 6h, 6 hours (n=8 and 14); 12h, 12 hours (n=10 and 11); 3d, 3 days (n=10 and 10); 1w, 1 week (n=15 and 14); and 2w, 2 weeks (n=15 and 15) for vehicle (open columns) and Ang II (solid columns), respectively. B, BNP promoter activity, expressed as the relative ratios of luciferase to ß-galactosidase: 2h (n=16 and 12), 6h (n=15 and 16), 12h (n=16 and 16), 3d (n=16 and 18), 1w (n=13 and 15), and 2w (n=21 and 22), vehicle (open columns) and Ang II (solid columns), respectively. Values are mean±SEM. *P<0.05 and ***P<0.001 Ang II vs vehicle.

Activation of a -2200-bp BNP Promoter by Ang II–Induced Pressure Overload
The BNP promoter activity was increased 3.9-fold (P<0.05) and 2.0-fold (P<0.001) at 2 and 6 hours, respectively, in response to Ang II infusion (Figure 2B). At 12 hours after starting the infusions, the BNP promoter activity did not differ between the vehicle- and Ang II–treated groups. Thereafter, Ang II infusion significantly augmented the BNP promoter activity by 1.7-, 2.4-, and 2.8-fold, at 3 days, 1 week, and 2 weeks, respectively (Figure 2B). The effect was sequence specific, as illustrated by the absence of Ang II–stimulated increases in transcription directed by the proximal BNP promoter (-114-bp fragment, data not shown).

BNP AP-1 Binding Activity in the Left Ventricle
Gel mobility shift assays were used to analyze the time-course of BNP AP-1 binding activity in response to Ang II infusion. BNP AP-1 DNA binding activity was increased 2.7- and 1.9-fold at 2 and 6 hours, respectively (Figure 3A). Later, BNP AP-1 binding activities were not statistically significantly different between the vehicle- and Ang II–treated rats. The specificity of AP-1 binding was confirmed by competition and supershift analysis (Figure 3B).

View larger version (37K): [in this window] [in a new window]   Figure 3. A, BNP AP-1 DNA binding activities in response to Ang II infusion: vehicle (open columns) and Ang II (solid columns). For number of experiments, see Figure 2A. Values are mean±SEM. *P<0.05 and ***P<0.001 Ang II vs vehicle. B, Effect of Ang II infusion for 6 hours on BNP AP-1 binding activity. Competition analysis indicates that AP-1 binding activity was inhibited by unlabeled AP-1 oligonucleotide (lane 3), whereas nonrelated DNA Oct-1 (lane 4) or mutated AP-1 site (lane 5) had no effect on DNA binding. Binding reactions were incubated with 1 µg of c-fos (4) (lane 7), c-fos (K25) (lane 8), and c-Jun/AP-1 (lane 9). The presence of Jun B/N17 (lane 10) and Jun D/329 (lane 11) was detected in the complex formed between BNP AP-1 probe and nuclear extracts from Ang II–treated left ventricles.

	Discussion

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The results of the present study show that left ventricular BNP mRNA and ir-BNP levels are distinctly regulated from the BNP promoter activity in Ang II–induced model of experimental hypertension in vivo. In rats, infusion of Ang II induces hypertension and expression of various cardiac genes including BNP.²⁶ In our study, Ang II infusion increased blood pressure and ventricular weight–to–body weight ratio and induced changes in diastolic function without any effects on systolic function. Interestingly, despite constant increase in blood pressure and cardiac mass, BNP mRNA levels were only temporarily upregulated and returned to the control levels within 3 days. Left ventricular BNP peptide concentrations followed the changes in BNP mRNA levels. In contrast to the present results, the left ventricular BNP mRNA and peptide levels were similar to those of controls in deoxycorticosterone salt–treated rats after 1 week, whereas they were increased after 5 weeks.¹⁶ Thus, in the Ang II–induced hypertension model, BNP gene expression may also be upregulated during the later phase of ventricular hypertrophy, the aspect that was not evaluated in this study. Yet, transgenic rats overexpressing human renin and angiotensinogen genes have normal left ventricular BNP mRNA levels even in established phase of hypertension and severe myocardial hypertrophy.¹⁸ Lack of an increase in ventricular BNP mRNA levels has also been observed in some patients with heart failure.^19,20

To determine whether alterations in the rate of transcription of the BNP gene could account for the changes observed in BNP mRNA levels, we measured the activity of a -2.2-kbp BNP promoter fragment fused to the luciferase reporter gene by injecting it directly into beating left ventricle. This portion of the BNP promoter is sufficient to direct cardiac-specific expression in vitro²² and in vivo in transgenic mice (S. Bhalla and M. Nemer, 2001, unpublished observations). Ang II infusion increased BNP promoter activity within 2 hours, and the promoter activity remained upregulated throughout the 2-week follow-up period, except at 12 hours. This finding provides direct in vivo evidence for pressure overload–mediated transcriptional regulation of BNP gene expression. Importantly, however, the peak increase in BNP mRNA levels was noted after 12 hours, at the time when the activity of BNP promoter did not differ between vehicle- and Ang II–treated rats. Moreover, BNP mRNA and ir-BNP levels reduced gradually to control levels, despite persistent upregulation of BNP gene transcription from 3 days to 2 weeks. These divergences between the BNP promoter activity and BNP mRNA and peptide levels suggest that posttranscriptional control plays an important role in the regulation of BNP gene expression in vivo.

BNP mRNA, like many other rapidly expressed genes, contains several AU-rich elements (sequences rich in A and U nucleotides) in the 3'-untranslated region²⁷ that may be involved in the translation-dependent mRNA degradation.²⁸ The observation that activators of protein kinase C and mitogen-activated protein kinases in cell culture models of myocyte hypertrophy enhance BNP transcript stability^29,30 is consistent with a role for posttranscriptional regulation. Protein kinase C activation results in the accumulation of c-fos protein, which interacts with Jun family members to constitute AP-1 activity.³¹ Because Ang II has been shown to activate protein kinase C and mitogen-activated kinases and to stimulate AP-1 activity in cardiac myocytes in vitro,²⁶ we examined whether BNP AP-1 binding activity in the nuclear extracts of left ventricles paralleled with changes of the BNP mRNA levels. BNP AP-1 binding activity increased significantly at 2 hours of Ang II treatment but decreased to control levels within 12 hours. Because the normalization of AP-1 binding activity preceded the decrease of BNP mRNA levels, one possibility is that decreased stabilization of mRNA during prolonged Ang II infusion could explain the fall of BNP mRNA to control levels. Nevertheless, further studies are needed to characterize the precise posttranscriptional mechanisms mediating the changes in BNP gene expression.

In patients with congestive heart failure, plasma BNP levels are elevated according to the severity of left ventricular dysfunction.^3,4 In the present study, plasma ir-BNP levels peaked at 12 hours after starting Ang II infusions and remained increased until the end of the experiment. The raised plasma BNP concentrations in the absence of increased ventricular BNP mRNA and peptide levels might be explained by enhanced BNP translational efficiency or capacity. However, increased release of BNP from atria⁸ and decreased elimination of BNP from the circulation,^1,2 which were not measured in this study, could also result in increased plasma BNP concentrations. Furthermore, complex interactions regulating blood pressure and myocardial hypertrophy are involved in this experimental model of hypertension; ie, Ang II itself and other mediators of the neurohumoral response to the rapid rise in mean arterial pressure can have many effects on plasma BNP levels and cardiac BNP gene expression, and these may be specific to Ang II–induced hypertension. Multiple factors involved in regulating hemodynamics in this model were reflected by the initial fall in heart rate, which was probably owing to sympathetic inhibition and parasympathetic activation caused by the baroreceptor response to the initial increase in blood pressure. The subsequent rise in heart rate may represent a gradual loss of baroreceptor sensitivity and facilitation of release of norepinephrine from cardiac sympathetic nerve terminals.²⁶

In conclusion, we show here for the first time that posttranscriptional control play an important role in the regulation of left ventricular BNP gene expression in vivo. This could, in part, explain the conflicting results regarding left ventricular BNP gene expression in patients with cardiac disease and in various experimental models of hemodynamic overload. Our results also suggest that posttranscriptional mechanisms may contribute to blood BNP concentration used in the diagnosis of heart failure.

	Acknowledgments

 
This work was supported by grants from the Academy of Finland, Sigrid Juselius Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Medical Foundation, the Aarne Koskelo Foundation, the Ida Montin Foundation, and the Canadien Institute for Health Research. We thank Sirpa Rutanen, Tuula Inkala, Pirjo Korpi, Tuula Lumijärvi, Ulla Weckstöm, and Xiao Ping for expert technical assistance.

Received September 24, 2001; first decision November 2, 2001; accepted December 27, 2001.

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