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Am J Physiol Heart Circ Physiol 290: H1635-H1641, 2006. First published November 4, 2005; doi:10.1152/ajpheart.00612.2005
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Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

Tue E. H. Christoffersen,1 Mark Aplin,3 Claes C. Strom,3 Soren P. Sheikh,3 Ole Skott,5 Peter K. Busk,4 Stig Haunso,1 and Lars B. Nielsen2

1Laboratory of Molecular Cardiology, 2Department of Clinical Biochemistry, and 3Laboratory of Molecular and Cellular Cardiology, Department of Medicine B, Rigshospitalet, Copenhagen; 4Department of Virology and Molecular Toxicology, Novo Nordisk A/S, Maalov; and 5Department of Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark

Submitted 8 June 2005 ; accepted in final form 28 October 2005


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg·kg–1·day–1) to investigate a possible role of the renin-angiotensin system in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding increased left ventricular expression of NPR-A and NPR-C mRNA by 110% (P < 0.001) and 520% (P < 0.01), respectively, after 8 wk; as expected, it also increased the expression of ANP and BNP mRNAs. Losartan induced a slight reduction of left ventricular weight but did not affect the expression of mRNAs for the natriuretic peptides or their receptors. Although increased gene expression does not necessarily convey a higher concentration of the protein, the data suggest that pressure overload is accompanied by upregulation of not only ANP and BNP but also their receptors NPR-A and NPR-C in the left ventricle.

losartan; angiotensin II type 1 receptor; renin

CARDIAC LEFT VENTRICULAR HYPERTROPHY (LVH) is a risk factor for cardiovascular morbidity and mortality (28). LVH develops in response to increased cardiac workload. In maintenance of chronic LVH, such as in hypertension or aortic stenosis, the activity of the intracardiac renin-angiotensin system is increased, resulting in augmented formation of ANG II (19). ANG II activates the ANG II type 1 receptor (41) and regulates multiple physiological processes in the cardiovascular system, including cardiac fibrosis and growth (1). Blocking the ANG II type 1 receptor inhibits these responses (47) and decreases LVH independently of changes in the systemic blood pressure (5).

Expression of the atrial (ANP) and brain (BNP) natriuretic peptides is significantly increased in animal models of chronic hemodynamic overload (15). A third natriuretic peptide, C-type natriuretic peptide (CNP), is primarily expressed in the nervous system and vascular endothelial cells. One study suggested that CNP may be produced in excess in the failing heart (24). ANP and BNP have natriuretic and vasorelaxant properties, as demonstrated by studies in genetically modified mice with disruption of the gene encoding ANP (23) or overexpression of BNP (37). Also, ANP and BNP are important autocrine/paracrine modulators of cardiac growth and remodeling (22, 46).

The biological activity of ANP and BNP is conveyed by binding to natriuretic peptide receptor (NPR)-A (45). Hence, mice lacking this receptor display cardiac fibrosis and hypertrophy from birth (10). CNP binds NPR-B (45) and has been proposed to inhibit myocardial fibroblast proliferation and activation (6, 17). Binding of any of the natriuretic peptides to the third natriuretic peptide receptor, NPR-C, leads to internalization and lysosomal degradation of the peptide-receptor complex (45). Thus NPR-C probably primarily functions as a clearance receptor (32, 34, 40). The systemic and tissue levels of natriuretic peptides may also be regulated by endothelial neutral endopeptidase (NEP), which degrades the natriuretic peptides (9, 11).

It is not known whether expression of the NPRs is regulated in established pressure-overload LVH. Because natriuretic peptide signaling modulates cardiac growth and fibrosis, we investigated the effect of ascending aorta banding in rats on the expression of the genes for natriuretic peptides and their receptors. Previous studies suggest that the renin-angiotensin system interferes with natriuretic peptide gene expression (16, 27). Hence, we also investigated the effect of blockade of the ANG II type 1 receptor with losartan.


   METHODS
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 METHODS
RESULTS
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Animals. Male Wistar rats (n = 97) weighing 70–90 g were obtained from Møllegaard Breeding Center (Lille Skensved, Denmark), kept at Rigshospitalet with a 12:12-h light-dark cycle, and fed standard rat chow. During Hypnorm/Dormicum (0.2 ml/100 g sc; Boehringer Ingelheim, Ingelheim, Germany) and 1–1.5% isoflurane (Abbott Laboratories, Abbott Park, IL) anesthesia the ascending aorta was exposed by left-side thoracotomy, and a titanium clip with an inner diameter of 0.6 mm was placed 5 mm above the aortic valves with a custom-made applier (Weck Closure Systems, Research Triangle Park, NC) (43). Sham-operated animals underwent the same procedures except for the placement of the clip. The overall mortality was ~13%. All protocols were in accordance with institutional guidelines and were approved by the Danish Animal Experimentation Inspectorate under the Ministry of Justice.

Rats with ascending aortic banding were randomized to losartan (10 mg·kg–1·day–1; Merck, Whitehouse Station, NJ) or vehicle (isotonic saline) 4 wk after surgery. In conscious normotensive rats losartan (DuP753) given orally at a dose of 10 mg/kg inhibits the pressor response to intravenous ANG II from 50 mmHg to <10 mmHg (50, 51). Sham-operated control rats received vehicle. Losartan and vehicle were administered continuously with subcutaneous osmotic minipumps (Alzet, Cupertino, CA). After 1, 2, or 4 wk of treatment the hearts were excised. The left ventricle was separated and weighed before being frozen in liquid nitrogen and stored at –80°C. A time course of 8 wk in total was chosen to avoid heart failure confounding the study. Thus previous evidence indicates that ascending aorta banding in rats does not lead to the development of heart failure until 8–9 wk and onwards (12, 30, 42). We did not commence losartan treatment at the time of surgery, because we aimed at studying the effect of losartan on established LVH (hypertrophy develops within 2 wk after banding). Thus the effect of losartan on established LVH was conceived to be clinically more important than a putative effect of losartan on the induction of LVH during the initial weeks after aortic banding. The 5 and 6 wk time points were chosen to investigate a possible early effect of losartan on established hypertrophy.

Total RNA purification and cDNA amplification. Total RNA was isolated from 50–100 mg of tissue with Tri Reagent (Molecular Research Center, Cincinnati, OH) after homogenization with a Mixer Mill 300MM (Retsch, Haan, Germany). RNA integrity was ensured by 1.4% agarose gel electrophoresis. RNA purity and concentration were determined by A260 and A280 measurement. First-strand cDNA was synthesized from 2 µg of total RNA with random hexamer primers and the Omniscript RT kit (Qiagen, Durham, NC).

Quantitation with real-time PCR. Quantitative real-time PCR analyses were performed with the Rotor-Gene 3000 (Corbett Research, Mortlake, Australia) and the Quantitect SYBR Green PCR kit (Qiagen). The primers were GAPDH: 5'-GTCGGTGTGAACGGATTTG-3', 5'-CTTGCCGTGGGTAGAGTCAT-3'; ANP: 5'-CCGGTACCGAAGATAACAGC-3', 5'-CTCCAGGAGGGTATTCACCA-3'; BNP: 5'-GCAGAAGCTGCTGGAGCTGC-3', 5'-GATCCGCGGAAGGCGCTGTCT-3'; CNP: 5'-AATACAAAGGCGGCAACAAG-3', 5'-CACAGTGCAGTTCCCAATCC-3'; NPR-A: 5'-CCTTTCAGGCTGCCAAAAT-3', 5'-ATCCTCCACGGTGAAGTTGA-3'; NPR-B: 5'-TCTATGCCAAGAAGCTGTGG-3', 5'-CCAGGCCTTCCAAGTAGAAA-3'; NPR-C: 5'-TGACACCATTCGGAGAATCA-3', 5'-CATCTCCGTAAGAAGAACTGTTGA-3'; and NEP: 5'-AAAAGGTGGACAAAGATGAGTG-3', 5'-TGCCCCCATAGTTCAATGAGT-3'. The specificity of each set of primers was ensured by 1.4% agarose gel analysis and DNA sequence analysis (GATC Biotech, Konstanz, Germany). Each PCR contained cDNA synthesized from 10 ng of total RNA. Parallel analyses of dilutions of a pool of heart cDNA were used to determine the relation between the time point of the log-linear increase of the fluorescence signal and the concentration of an mRNA transcript. All mRNAs were quantitated twice in separate analyses; interassay coefficients of variation were 14% (GAPDH), 12% (ANP), 14% (BNP), 12% (NPR-A), 12% (NPR-B), 12% (NPR-C), and 6% (NEP). The results were normalized to the content of GAPDH within the same sample (8, 13, 14).

Plasma renin measurements. Plasma renin concentrations were measured as previously described (31). Only results with linearity in serial dilutions (between 50 and 1,000 fold) were accepted. The assay was calibrated with renin standards from the National Institutes for Biological Standards and Control (Potters Bar, UK), and results are expressed in Goldblatt units.

Statistics. Effects of aortic banding on measurements of cardiac size, plasma renin concentration, and mRNA expression were analyzed with two-way ANOVAs using time of euthanization and aortic banding as the independent grouping variables; losartan-treated rats were not included in these analyses. Effects of losartan in aorta-banded rats were analyzed with two-way ANOVAs using time of euthanization and losartan treatment as the independent grouping variables; sham-operated rats were not included in these analyses. There were no significant interactions between the two independent variables in any of the two-way ANOVA tests. Posttests were done by the Bonferroni method. Plasma renin concentration data were log-transformed before analyses. All statistics were done with GraphPad Prism version 4.0 for Windows (GraphPad Software, San Diego, CA). P < 0.05 was considered significant.


   RESULTS
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DISCUSSION
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Effects of ascending aorta banding and losartan on left ventricular weight and renin concentration. The ratios of left ventricular weight to body weight (LV/BW; ANOVA, effect of banding: P < 0.0001) and tibia length (LV/TL; ANOVA, effect of banding: P < 0.0001) were increased 80–90% in rats with aortic banding compared with the sham-operated group at 5–8 wk after aortic banding (Table 1). Losartan conferred a ~12% decrease in both LV/BW (ANOVA, effect of losartan: P = 0.06) and LV/TL (ANOVA, effect of losartan: P = 0.02) after 2 and 4 wk of treatment. The plasma renin concentration increased five- to ninefold in the losartan-treated (ANOVA, effect of losartan: P < 0.0001) compared with the placebo-treated rats with aortic banding (Table 1) and was elevated approximately twofold (ANOVA, effect of banding: P = 0.004) in the placebo-treated rats with aortic banding compared with the placebo-treated sham-operated group (Table 1).


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  		Table 1. Temporal effects of aortic banding and losartan treatment on left ventricular weight and plasma renin concentration

 
Effects of aortic banding and losartan on expression of genes for NPRs. The heart expression of NPR-A mRNA was increased 1.4-, 1.4-, and 2.1-fold (Fig. 1A; ANOVA, effect of banding: P < 0.0001) and that of NPR-C mRNA was increased 2.9-, 4.5-, and 6.2-fold (Fig. 1B; ANOVA, effect of banding: P < 0.0001) at 5, 6, and 8 wk, respectively, in placebo-treated rats with aortic banding compared with the placebo-treated sham-operated group. The expression of NPR-B mRNA was also slightly, but significantly, increased 1.1-, 1.2-, and 1.4-fold (ANOVA, effect of banding: P = 0.002) in placebo-treated rats with aortic banding compared with the placebo-treated sham-operated group (Fig. 1C). Losartan did not affect the expression of NPR-A, NPR-B, or NPR-C mRNA in the aorta-banded rats.


Figure 1
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  		Fig. 1. Left ventricular expression of mRNAs for natriuretic peptide receptors (NPRs) in rats with ascending aortic banding. The scatterplots show the expression of NPR-A (A), NPR-C (B), and NPR-B (C) in ascending aorta stenosis (AS) and sham-operated (S) rats. AS rats were treated with losartan (los) or placebo (plac) from week 4 after aortic banding. S rats were treated with placebo. Hearts were removed 5, 6, and 8 wk after banding. Each point represents values from an individual rat; lines with bars indicate means ± SE. The mRNA expression levels were determined in duplicate real-time PCR assays. The results are normalized to the GAPDH mRNA content in the same sample, and the results are expressed as a fraction of the mean of all in a run. Bonferroni post test: *P < 0.05, **P < 0.001 for the indicated 2-group comparisons.

 
Effects of aortic banding and losartan on NEP gene expression. The expression of NEP mRNA in rats with aortic banding was reduced to 40%, 93%, and 80% of that in sham-operated rats at 5, 6, and 8 wk, respectively (Fig. 2; ANOVA, effect of banding: P < 0.05). NEP mRNA expression was not affected by losartan.


Figure 2
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  		Fig. 2. Left ventricular expression of mRNA for neutral endopeptidase in rats with ascending aorta banding. The scatterplots show the expression of neutral endopeptidase in AS and S rats. AS rats were treated with losartan or placebo from week 4 after aortic banding. S rats were treated with placebo. Hearts were removed 5, 6, and 8 wk after banding. Each point represents values from an individual rat; lines with bars indicate means ± SE. The mRNA expression levels were determined in duplicate real-time PCR assays. The results are normalized to the GAPDH mRNA content in the same sample, and the results are expressed as a fraction of the mean of all in a run. Bonferroni post test: *P < 0.05 for the indicated 2-group comparison.

 
Effects of pressure overload and losartan on expression of genes for natriuretic peptides. Left ventricular ANP mRNA expression was increased 32-, 51-, and 72-fold (Fig. 3A; ANOVA, effect of banding: P < 0.0001) and BNP mRNA was increased 5-, 6-, and 5-fold (Fig. 3B; ANOVA, effect of banding: P < 0.0001) at 5, 6, and 8 wk, respectively. in placebo-treated rats with aortic banding compared with the placebo-treated sham-operated group. The CNP mRNA content in the left ventricle was very low, i.e., <1% of the level in the brain, and we did not see any effect of aortic banding on CNP expression (data not shown). Losartan did not affect the expression of ANP, BNP, or CNP mRNA at any time point.


Figure 3
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  		Fig. 3. Left ventricular expression of mRNAs for atrial (ANP) and brain (BNP) natriuretic peptides in rats with ascending aortic banding. The scatterplots show the expression of ANP (A) and BNP (B) mRNAs in AS and S rats. AS rats were treated with losartan or placebo from week 4 after aortic banding. S rats were treated with placebo. Hearts were removed 5, 6, and 8 wk after banding. Each point represents values from an individual rat; lines with bars indicate means ± SE. The mRNA expression levels were determined in duplicate real-time PCR assays. The results are normalized to the GAPDH mRNA content in the same sample; and the results are expressed as a fraction of the mean of all in a run. Bonferroni post test: **P < 0.001 for the indicated 2-group comparisons.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
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In the present study, ascending aorta banding in rats was used to investigate NPR gene expression during LVH. Of note, the cardiac hypertrophy in the ascending aorta-banded rat results in fully compensated left ventricular systolic function for at least 8 wk (12, 30, 42). The major findings were 40–110% and 90–520% increases in NPR-A and NPR-C gene expression, respectively, in the hypertrophic left ventricle.

Previous results suggest that ANP decreases NPR-A expression in cultured rat aortic smooth muscle cells (7). Thus it is noteworthy that the upregulation of left ventricular NPR-A mRNA expression in aorta-banded rats occurred in the setting of markedly (32- to 72-fold) elevated ANP mRNA concentration. In the present model there was no correlation between ANP and NPR-A mRNA expression, suggesting that ANP and NPR-A mRNA expression in vivo are independently regulated and perhaps both induced by the mechanical stimulus.

The finding of increased cardiac NPR-A mRNA expression is compatible with previous reports of increased NPR-A expression in hypertensive rats (27) and in rats in which the hearts were volume overloaded by an aortocaval shunt (4, 44). It should be noted that steady-state mRNA levels were measured and that the results may reflect increased gene transcription, decreased mRNA degradation, or a combination.

NPR-A is a receptor for both ANP and BNP and is expressed mainly in myocytes and fibroblasts (29) but is also found in cardiac endothelial cells (20, 49). Genetic ablation of the NPR-A gene in cardiac myocytes of mice results in cardiac hypertrophy as well as fibrosis from birth (10). In addition, it was recently reported that targeted overexpression of a dominant-negative NPR-A receptor in the suprarenal aorta-banded mouse heart results in increased cardiac hypertrophy and fibrosis (38). The ascending aorta-banded rat heart is also characterized by extensive hypertrophy and fibrosis (48). Although increased gene expression does not necessarily convey a higher concentration of the protein, it is conceivable that the observed increase in NPR-A mRNA expression reflects increased production of the NPR-A protein and that it participates in modulation of the myocardial response to pressure overload.

We also observed an increase in NPR-C mRNA expression after aortic banding. Cardiac expression of the NPR-C gene has been assigned to the same cells as the NPR-A gene, i.e., myocytes, fibroblasts, and endothelial cells (29). NPR-C has been proposed to regulate tissue levels of the natriuretic peptides (34), and changes in NPR-C gene expression may thus have important physiological consequences in the pressure-overloaded left ventricle. The finding of upregulation of NPR-C mRNA expression by pressure overload is in accordance with one previous study in a rat model of experimental hypertension (27). Interestingly, the effect of aortic banding on NPR-C mRNA expression appeared to increase with time (the elevation was 2.9-fold at 5 wk but 6.2-fold at 8 wk after aortic banding). A similar pattern was seen for ANP: the magnitude of the increase in ANP mRNA expression was 32-fold at 5 wk and 72-fold at 8 wk after aortic banding. Increased NPR-C gene expression may thus dampen the increased production of ANP and BNP in the pressure-overloaded left ventricle. It may seem contradictory that both NPR-A and NPR-C are upregulated in aorta-banded rats, when they may have opposing effects. However, NPR-C may confer signaling in addition to its proposed role as a clearance receptor (2). Also, NPR-A and NPR-C gene regulation do not necessarily occur in the same cells.

In the present study we investigated the gene expression of NPR-B and NEP. NEP was most pronouncedly reduced in the left ventricle at 5 compared with 6 and 8 wk after ascending aorta banding, whereas NPR-B mRNA was most pronouncedly upregulated 8 wk after aortic banding. The apparent time-dependent changes in gene expression may reflect ongoing myocardial remodeling involving altered NEP and NPR-B gene expression during the cardiac response to pressure overload. Clearly, further investigations of NEP and NPR-B expression at time points earlier and later than 5 and 8 wk after banding are needed to verify this hypothesis.

The plasma BNP concentration is elevated in cardiac hypertrophy (52) and correlates positively with left ventricular BNP mRNA (18). In patients with aortic stenosis, the plasma concentration of BNP is elevated to a larger extent than that of ANP (39). Thus we were surprised to see a much more marked upregulation of ANP (72-fold at 8 wk) than of BNP (5-fold at 8 wk) mRNA expression in the hypertrophic left ventricle. The results may simply reflect that the basal level of ANP mRNA expression is lower than that of BNP, but they could also to some extent reflect differential regulation of the two genes in the pressure-overloaded heart. Of note, McMullen et al. (35) described a similar pattern of relative ANP and BNP gene expression in the left ventricle of mice with ascending aorta stenosis.

The renin-angiotensin system probably plays a determining role in established pressure overload LVH, and pharmacological inhibition was previously reported to reduce LVH in rats with ascending aorta banding (5, 25, 26, 48). Of note, in this particular experimental model the effect has been ascribed to a direct effect of ANG II type 1 receptor blockade on myocardial cells because afterload remains unaffected by alterations in the systemic blood pressure (5, 33). Accordingly, when treatment with losartan was commenced 4 wk after banding of the ascending aorta, we observed a reduction in relative left ventricular weight already after 2 wk of treatment. The reduction in left ventricular weight by losartan, however, was rather small (~12%), and losartan did not significantly affect the expression of the mRNAs for either NPRs or the natriuretic peptides. Others have seen decreased expression of ANP and BNP mRNA after treatment of pressure-overload LVH in rats with losartan (33). In those studies, however, treatment was continued for longer time periods and given orally. It is therefore difficult to directly compare the results with our study. Nevertheless, in accordance with previous data (50) losartan was effective in inhibiting the renin-angiotensin system as judged from the plasma renin concentration, which was increased more than sixfold in losartan-treated compared with control rats. Thus the lack of effect of ANG II type 1 receptor blockade on ANP and BNP mRNA expression suggests that the previously reported effects of losartan are secondary to the regression of left ventricular mass. Indeed, in rats with suprarenal aortic banding left ventricular load may be the determining factor in regulation of left ventricular natriuretic peptide gene expression (36).

The major findings in the present study are that aortic banding increases left ventricular mRNA expression of NPR-A and NPR-C. If these changes are mirrored in increased numbers of functional membrane receptors, the data imply that not only changes in ANP and BNP concentrations but also changes in the number of NPRs may be important in growth and remodeling of the hypertrophic left ventricle during pressure overload. Increased number of NPR-A receptors may amplify beneficial paracrine/autocrine effects of ANP and BNP on the heart, whereas increasing expression of NPR-C may counteract this by enhancing the removal of the natriuretic peptides. Indeed, patients with chronic heart failure have increased NPR-C levels and lower plasma ANP (3), pointing to specific NPR-C blockade as a possible treatment strategy. In addition, ANP analogs that bind NPR-A selectively over NPR-C increase the physiological actions of ANP (21) and may thus also be useful in the treatment of LVH and heart failure.


   GRANTS
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 ABSTRACT
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 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by grants from the University of Copenhagen, the Danish Medical Research Council, The Birthe and John Meyer Foundation, Villadsen Family Foundation, Hjertecentrets forskningsfond, Den Lægevidenskabelige Forskningsfond for Storkøbenhavn, Færøerne og Grønland, Jeppe Juhl og Hustru Ovita Juhls Mindelegat, and Eva og Robert Voss Hansens Foundation.


   ACKNOWLEDGMENTS
 
We thank Pernille Gundelach and Inge Andersen for excellent technical assistance and the staff at the Department for Biostatistics at the University of Copenhagen. DuPont Merck generously provided losartan.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. E. H. Christoffersen, Laboratory of Molecular Cardiology, Rigshospitalet 9312, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark (e-mail: tue{at}rh.dk)

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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