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Laboratory of Cardiovascular Biochemistry, Centre de recherche, Centre hospitalier de l’Université de Montreal (CHUM) Montreal, Quebec, Canada
(Requests for offprints should be addressed to Marek Jankowski, Centre de recherche du CHUM-Hôtel-Dieu, Pavillon de Bullion (6-816), 3840 rue Saint-Urbain, Montreal, Quebec, Canada, H2W 1T8; Email: marek.jankowski{at}umontreal.ca)
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Abstract |
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, but not ERß, proteins paralleled the pregnancy-related cGMP changes in the LV. In contrast, ANP mRNA of the LV remained at control level throughout gestation but increased postpartum, whereas brain natriuretic peptide (BNP) expression declined at term and increased postpartum. The particulate GC natriuretic peptide receptors (GC-A and GC-B) transcripts were already lower at day 14 of gestation. Natriuretic peptide clearance receptor (NPR-C) transcript was not altered on days 7 and 14, but increased at term. We conclude that cGMP concentration in the rat LV is influenced by both NOS and natriuretic peptide systems and may be involved in the changes of LV contractility and hypertrophy that occur during rat gestation. |
Introduction |
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In response to elevated female steroid hormones during gestation, cardiac growth and contractility are modulated profoundly in parallel with changes in various hormones, electrolyte balance, blood volume and blood pressure (Granger 2002). Estrogens regulate cardiac hypertrophy by direct effects on the heart and by triggering the release of cardioprotective factors. Estrogen stimulates nitric oxide synthase (NOS) in various organs, including cardiac tissue, in association with an increase of cyclic guanosine monophosphate (cGMP) (Weiner et al. 1994), the second messenger of nitric oxide (NO). Three different isoforms of NOS catalyze the oxidation of L-arginine to citrulline and NO: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) NOS. Myocardial eNOS appears to be important under physiologic conditions in pregnancy, where it is involved in cardiac hypertrophy (Trochu et al. 2000). eNOS knockout mice develop the hypertrophic phenotype by 5 months of age, manifested as increased wall thickness (Barouch et al. 2002). Interestingly, cGMP levels in the LV are unaffected by eNOS gene knockout because of compensation of its synthesis by upregulated atrial natriuretic peptide (ANP) (Gyurko et al. 2000), indicating an interaction between NOS and natriuretic peptide systems in the LV.
ANP and brain natriuretic peptide (BNP) are mainly produced in cardiac atria and ventricles respectively, and both are released into the circulation and influence blood volume and pressure. Cardiac ANP expression is influenced by elevated estradiol during pregnancy and postpartum (Jankowski et al. 2001, Mukaddam-Daher et al. 2002). Brown et al.(1993) have shown that the transcriptional downregulation of heart natriuretic peptide receptors is associated with the development of hypertrophic cardiac pathology in the rat. Two natriuretic peptide receptors, guanylyl cyclase (GC)-A and GC-B (also known as NPR-A and NPR-B), are signal-transducing, single-pass transmembrane glycoproteins exhibiting ligand-dependent intrinsic GC activity (Tremblay et al. 2002, Kuhn 2003). ANP and BNP have been shown to bind preferentially to GC-A, while C-type NP (CNP) displays a greater affnity for GC-B (Koller et al. 1991, Suga et al. 1992). A third receptor, NPR-C, lacks the GC domain, and modulates natriuretic peptide concentration through local metabolism (Nakao et al. 1993). The GC-A system has intrinsic growth inhibitory properties in cardiac fibroblasts (Cao & Gardner 1995), and ANP and BNP inhibit cardiac ventricular myocyte hypertrophy to a greater extent than NO (Horio et al. 2000), independently of blood pressure (Kishimoto et al. 2001). It is noteworthy that inactivation of GC-A, resulting in hypertension, cardiac hypertrophy and increased mortality, evokes gender disparity, suggesting a protective action of estrogen (Vuolteenaho & Ruskoaho 2003). Although the natriuretic peptide system is recognized as a critical factor in the control of cardiac hypertrophy (de Bold et al. 2001), few studies have investigated this action during pregnancy.
The purpose of this study was, therefore, to investigate the expression of natriuretic peptides, NOS and cGMP in the rat LV throughout gestation and early postpartum. Because of their contribution to ANP and NO release in the cardiovascular system, estrogen and oxytocin receptors (OTR) were also evaluated (Gutkowska et al. 1999, Jankowski et al. 2001, Mukaddam-Daher et al. 2001, Wang et al. 2003). Our results demonstrate that cGMP concentration in the rat LV is controlled by both NOS and natriuretic peptides, but their inverse expressions at different stages of gestation suggest distinct roles in the control of physiologic cardiac hypertrophy.
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Materials and Methods |
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These experiments were performed in accordance with the Guidelines of the Canadian Council on Animal Care, after approval of the animal care committee of the Centre hospitalier de l’Université de Montréal. Female Sprague–Dawley rats purchased from Charles River (St Constant, QC, Canada) were housed in a temperature- and light-controlled room with food and water available ad libitum. Age-matched virgin and pregnant animals were weighed and killed by decapitation at days 7, 14 or 21 (term) of gestation, and at days 1 or 4 postpartum. Hearts were quickly removed, dissected, and blotted dry. Heart atria and ventricles were separately weighed, and then frozen in liquid nitrogen, and stored at –80 °C for RNA or protein extraction.
Ventricular cGMP assay
Measurement of cGMP concentration has already been described (Gutkowska et al. 1999). Briefly, the dissected tissues were cut into small pieces and homogenized in 5 vol of ice-cold 5% (v/v) trichloroacetic acid (TCA). The homogenates were centrifuged at 600 g, for 5 min, at 4 °C. TCA was extracted from the reaction mixture with 1:1 triocytydylamine and 1,1,2-trichlorofluoroethane (Sigma). cGMP concentration of the aqueous phase was quantified by radioimmunoassay, as described previously (Gutkowska et al. 1999), and expressed as picomoles per wet tissue weight in grams. The intra- and interassay coefficients of variation of this assay were 8% and 15% respectively.
Northern blot analysis
RNA was extracted from the LV with Trizol (Life Technologies, Gaithersburg, MD, USA), according to the manufacturer’s instructions. Total RNA was subjected to electrophoresis on 1.5% agarose gels containing 0.22 M formaldehyde and transferred onto nylon membranes (Hybond N+; Amersham) by capillary blotting. Immobilized RNA samples were hybridized with randomly primed 32P-cDNA probes corresponding to ANP and alpha-tubulin mRNA sequences. The probes were labeled with a random priming kit (Gibco BRL, Bethesda, MD, USA) and 32P-dCTP (3000 Ci/mmol; Amersham). The Pst 1-digested 660-bp fragment from plasmid clone PN-1–11 served as the ANP probe (a gift from Dr Mona Nemer, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada).
Complementary DNA synthesis and semiquantitative polymerase chain reaction (PCR)
Total RNA was reverse transcribed by Moloney murine leukemia virus reverse transcriptase (200 U; Life Technologies), with random primers (200 ng) in a 20 µl reaction mixture. To compare different expression levels, semiquantitative PCR was performed. A volume of 10 µl first-strand cDNA was added to a PCR mixture and amplified for 25–35 cycles by incubation at 95 °C for 1 min, at 57–65 °C for 1 min, and at 72 °C for 1.5 min, with a final incubation at 72 °C for 3 min, all in a Robocycler gradient 40 thermocycler (Stratagene, La Jolla, CA, USA). The RT reaction products were subjected to PCR amplification with the following primers:
The specificity of the amplified products was verified by sequencing. Amplification of 18S RNA, used as an internal standard, followed the manufacturer’s protocol (Ambion, Austin, TX, USA). PCR products were fractionated onto 1.2% agarose gels containing ethidium bromide. The signal intensities were measured in at least eight individual animals with two independent reverse transcriptions (RT) per sample. The intensity of the bands was determined by densitometry with Molecular Imaging Software (Image-Quant Software, Molecular Dynamics, Sunnyvale, CA, USA). To validate this RT-PCR assay as a tool for the semiquantitative measurement of mRNA, dose–response curves were established for different amounts of total RNA extracted from the rat LV, and the samples were quantified in the curvilinear phase of PCR amplification. The expression levels were normalized against 18S or GAPDH. No difference was observed in 18S or GAPDH levels at any stage.
Western blot analysis
Western blot analysis was conducted as described elsewhere (Wang et al. 2003). Proteins were separated on an 8% sodium dodecyl sulfate gel and electrotransferred to nitrocellulose membranes (Hybond-C; Amersham Pharmacia Biotech, Baie d’Urfé, QC, Canada). Unbound sites were blocked overnight at 4°C with 10% (w/v) nonfat milk in Tris–buffered saline containing 20 mmol/l Tris–HCl (pH 8.0), 140 mmol/l NaCl and 0.05% (w/v) Tween-20. The membranes were then probed with mouse monoclonal antibodies for iNOS or eNOS (BD Biosciences, San Jose, CA, USA). OTR were investigated with rabbit polyclonal antibodies (generous gift from Dr Kate Whittington, University of Bristol, UK), and estrogen receptors using rabbit polyclonal antibody (Research Diagnostics, Pleasant Hill, NJ, USA). The membranes were washed and incubated with secondary antibodies linked to horseradish peroxidase-labeled antimouse or antirabbit immunoglobulin G (Amersham Pharmacia Biotech) for 2 h. The blots were developed in an enhanced chemiluminescence system (Amersham Pharmacia Biotech) and visualized by exposure to Kodak radiographic film. The accuracy of protein loading on the gel was verified by reprobing with rabbit ß-actin antibody and protein coloration on the membranes. Density of bands was measured with the Scion program (NIH, Bethesda, MD, USA).
Immunocytochemistry (ICC)
Prior to ICC, OTR and ER antigenic sites were retrieved by immersing the sections in citrate buffer 0.1 M, pH 6.0, heated to 90 °C for 20 min and allowed to cool slowly to room temperature. For incubation, primary antibodies diluted 1/300 in blocking solution (No. 00–8020; Zymed Laboratories, San Francisco, CA, USA) were revealed by the biotin–streptavidin method (No. 95–999, Histostain-DS; Zymed Laboratories) (Jankowski et al. 2004). Controls obtained by the omission of primary antibodies were negative, emphasizing the specificity of ICC.
Statistical analysis
The data are expressed as mean ± S.E.M. Normalized data of nonpregnant, pregnant and postpartum groups were compared by ANOVA, followed by Dunnett’s test or, in the case of comparison with only one group, by a two-tailed version of Student’s t-test. P< 0.05 was accepted as the level of significance. For calculations, Prism 3 program was applied (GraphPad Software, San Diego CA, USA).
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Results |
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Table 1
shows that, compared with nonpregnant controls, rat body weight increased on gestational days 14 (223 ± 3 to 264 ± 6 g or 118%; P< 0.05) and 21 (412 ± 8 g, 184%; P< 0.001). LV mass increased in a similar manner. Figure 1 shows a positive correlation between LV weight and body weight. On gestational day 14, mean LV weight was 755 mg (112% of nonpregnant levels), and was further increased to 866 mg (128%) on day 21. As shown in Table 1, body weight remained above the control value on days 1 and 4 postpartum (127% and 132% respectively), and was associated with increments in ventricular weight (127% and 123%; P< 0.05). A positive correlation (r=0.81 and 0.73, respectively) between LV weight and body weight was found.
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cGMP concentration in the LV of nonpregnant and pregnant rats
Compared with nonpregnant rats, cGMP concentration was highest in the LV on day 14 of gestation (2.98 ± 0.05 vs 4.65 ± 0.17 pmol/g wet weight) and then decreased at term to 2.32 ± 0.10 pmol/g. cGMP concentration in the LV was elevated on postpartum days 1 and 4 (6.01 ± 0.15 and 9.21 ± 1.79 pmol/g respectively) (Fig. 2).
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In parallel with gestation-associated changes in LV cGMP levels, changes in OTR, iNOS and eNOS proteins were observed. Figure 3 shows that OTR (67 kDa)-, iNOS (135 kDa)- and eNOS (140 kDa)-specific proteins in the LV were elevated on days 7 and 14 of pregnancy as compared with nonpregnant controls. However, at term, the expression of these proteins was decreased three to four times below LV levels in nonpregnant controls, and then increased after parturition, to exceed control values on postpartum day 4. As presented in Fig. 4, the ER were slightly higher on gestational day 14 (35%), but were below control level (–60%) at postpartum. Western blot analysis detected no changes in ERß during pregnancy and postpartum.
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shows immunolocalization of OTR around the uterine lumen, within epithelial cells (small arrow), uterine glands (medium arrow) and myometrial smooth muscles (large arrow). ER immunoreactivity was also detected in cell nuclei of atrial cardiomyocytes (arrows in Fig. 5C). Much lower ER immunoreactivity could be detected in the heart ventricle (Fig. 5D). These results, confirming already known sites of OTR and ER expression, indicate antibody specificity. In addition, no ERß staining was observed in the rat heart sections.
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ANP mRNA expression in LV was not altered throughout gestation (Fig. 6A), but significantly increased postpartum. The results obtained by RT-PCR confirmed the Northern blot analysis and showed twofold increase in ANP mRNA in the LV of postpartum rats (Fig. 6B). Similarly, RT-PCR analysis revealed that BNP mRNA was unchanged on day 7, and then decreased to 60% by day 14, and further to 10% at term, as compared with nonpregnant controls considered as 100% (Fig. 6C). In the early postpartum period, LV BNP mRNA returned to control levels.
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Figure 7 presents the results of RT-PCR analysis of GC-A, GC-B, and NPR-C mRNA expression in LV of nonpregnant and pregnant rats in different stages of gestation and postpartum. Notably, compared with nonpregnant controls, GC-A mRNA, transducing ANP and BNP signals, was downregulated on days 14 and 21 of pregnancy, and in the early postpartum period (Fig. 7A). GC-B mRNA was also significantly lower in the LV at day 21 and postpartum than in nonpregnant controls (Fig. 7B). In contrast, NPR-C mRNA responsible for natriuretic peptide clearance (Fig. 7C) was significantly higher on day 21 of gestation.
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Discussion |
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and OTR proteins, but not with the expression of ERß, natriuretic peptides and their receptors. At term, LV cGMP decreases as does the expression of cardiac genes involved in particulate and soluble GC activities. These include natriuretic peptides, their GC receptors, eNOS, iNOS, and OTR. In contrast, the ventricular NPR-C transcript is elevated, suggesting that augmented cardiac natriuretic peptide clearance occurs at term. At postpartum, the cGMP-generating systems are activated, in parallel to a gradual decrease in cardiac hypertrophy. It is established that cardiac adaptations occur in pregnancy. The LV increases in mass to preserve contractile function when cardiac workload is increased to accommodate pregnancy-associated plasma volume expansion (Churchill et al. 1980, Atherton et al. 1982, Barron 1987). Vascular and cardiac adaptations during pregnancy are influenced by reproductive hormones. The actions of estrogens and progesterone are mediated by specific binding sites in vascular tissue and in the heart. Their hormonal effects include changes in the synthesis or release of cardiac natriuretic peptides, and in the oxytocin system (Mukaddam-Daher et al. 2002, Wang et al. 2003) as well as NOS and cGMP regulation (Weiner et al. 1994, Linke et al. 2002). In addition, direct interaction between these systems may also be involved in pregnancy-associated cardiac remodeling.
Parallel changes of the expression of LV NOS and OTR were observed during gestation and postpartum. These findings are consistent with OTR influencing NO activity, as previously demonstrated in the dog heart (Mukaddam-Daher et al. 2001), and with the predominant expression of OTR in endothelial cells of coronary arteries, providing a morphologic basis for eNOS and OTR interactions in the heart chambers (Jankowski et al. 2004).
An earlier report indicates that eNOS is transiently elevated during pregnancy in rats, and the increase is associated with enhanced NO-dependent control of myocardial oxygen consumption at a time when cardiac output is augmented (Linke et al. 2002). Despite a significant increase in eNOS protein expression at day 7 of pregnancy, the investigators observed a nonsignificant trend toward increased myocardial oxygen consumption. Similarly, in the present study, at day 7 of gestation, LV cGMP tended only to increase, despite the significant increases in eNOS proteins. There is no explanation for this lack of parallelism between eNOS and cGMP production. A delay in pregnancy-associated eNOS phosphorylation is a plausible explanation that remains to be proven.
Interestingly, we found that cGMP increased in the LV at day 14 of gestation in parallel with increments of eNOS and OTR, but low expression of GC-A and GC-B mRNAs. Downregulation of cardiac natriuretic peptide receptors in LV during pregnancy may be physiologically required to control the negative inotropic activity of natriuretic peptides and to allow the development of pregnancy-induced LV hypertrophy. The mechanism of low expression of GC-A and GC-B mRNAs in this period is not known; however, it may be explained by two hypotheses. First, alterations of female steroids during pregnancy can downregulate natriuretic peptide receptors in several organs (Vaillancourt et al. 1997, 1998). The presence of ERs in the isolated cardiac myocytes and fibroblasts (Grohe et al. 1997) and the fact that these cells contain functional natriuretic peptide receptors suggest that ERs may be involved in pregnancy-mediated changes in the heart. The present ICC data indicate that the density of ERs receptors is much lower in cardiac ventricles than in atria. However, these receptors are functional and stimulate ANP expression and cGMP production in cultured rat cardiomyocytes (Babiker et al. 2004). We have demonstrated that ER, but not ERß, changes during pregnancy. These ER receptors are, to some extent, upregulated at midgestation in association with similar cGMP elevation. We have already demonstrated that ovarian natriuretic peptide receptors may be a target of estrogen action (Jankowski et al. 1997, Gutkowska et al. 1999). A similar effect in the heart may be proposed where natriuretic peptide receptors exert their physiologic effect on both myocytes and nonmyocytes (Cao & Gardner 1995), and where natriuretic peptide-signaling events have been detected in both cell types. Second, it has already been shown that downregulation at the level of GC-A transcription appears to depend on intracellular increases of cGMP, and not on the natriuretic peptide ligand itself (Cao & Gardner 1995). Functional analysis of the GC-A promoter has demonstrated that long-term negative regulation of GC-A occurs via a putative cGMP-responsive element located at more than 1 kbp upstream of the transcription start site (Roubert et al. 1987, Tremblay et al. 2002).
The importance of cGMP in the control of transient LV hypertrophy and the changes in contractility during pregnancy remain to be clarified. Evidence from animal and human studies suggest that the cGMP signaling pathway is gestationally regulated (Weiner et al. 1994, Linke et al. 2002). We observed that, at term, LVcGMP declined below nonpregnant control levels, confirming the previous report by Weiner et al.(1994). This decrease in cGMP may have resulted from downregulated natriuretic peptides and their GC receptors, as well as upregulated clearance receptors, which act as a buffering system, reducing the effective pool of natriuretic peptides. Decline of LV OTR, eNOS, iNOS and ER, and, as we have reported previously, plasma ANP (Mukaddam-Daher et al. 2002) may also contribute to cGMP reduction in the LV. The reduced levels of cGMP at term favor a shift of balance toward enhanced heart work at the onset of labor. Therefore, cGMP may play an important role in maintaining cardiac quiescence during the final period of pregnancy, and a decrease in cGMP at term may contribute to the increase in heart rate and contractility during active labor.
Finally, an important and still unresolved issue is whether cGMP produced by particulate versus soluble GC acts differently inside the cells. For instance, the increase in cGMP mediated by ANP, but not by NO, prevents cardiomyocyte hypertrophy (Horio et al. 2000). It has also been shown that particulate GC-A, but not soluble GC, has potent effects on plasma membrane control of the calcium ATPase pump (Zolle et al. 2000). A recent study has also demonstrated that ANP/GC-A, but not NO/soluble GC, stimulates the translocation of PKG I to the plasma membrane (Airhart et al. 2003). It is hypothesized that cGMP-mediated signaling is compartmentalized within cells targeted by NO and natriuretic peptides (Kuhn 2003).
In conclusion, these findings imply that during pregnancy, LVNOS and natriuretic peptide systems exert direct actions on the heart, and are thus involved in adaptation to pregnancy-associated volume alterations.
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Acknowledgements |
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Funding |
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This work was supported by grants from the Canadian Institutes of Health Research (MT-11674, MOP-62901 to J G and S M-D, as well as MT-15049, MOP-53217 to M J and J G), and the Canadian Heart and Stroke Foundation to J G and S M-D. There is no conflict of interest in this research.
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References |
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Received 12 October 2004
Accepted 19 October 2004
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