This Article Abstract Full Text (PDF) All Versions of this Article: 44/5/746    most recent 01.HYP.0000144801.09557.4cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Franco, V. Articles by Perry, G. Search for Related Content PubMed PubMed Citation Articles by Franco, V. Articles by Perry, G. Related Collections Structure Contractile function Other heart failure Remodeling Other hypertension Heart failure - basic studies Physiological and pathological control of gene expression

(Hypertension. 2004;44:746.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Atrial Natriuretic Peptide Dose-Dependently Inhibits Pressure Overload-Induced Cardiac Remodeling

Veronica Franco; Yiu-Fai Chen; Suzanne Oparil; Ji An Feng; Dajun Wang; Fadi Hage; Gilbert Perry

From the Vascular Biology and Hypertension Program (V.F., Y.-F.C., S.O., J.A.F., D.W., F.H., G.P.), Division of Cardiovascular Disease, University of Alabama at Birmingham, and the Cardiology Section (G.P.), Birmingham VA Medical Center, Birmingham, Ala.

Correspondence to Veronica Franco, MD, University of Alabama at Birmingham, ZRB 1024, 703 19th St S, Birmingham, AL 35294. E-mail vfranco{at}uab.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
We hypothesized that a single copy of the proatrial natriuretic peptide gene (Nppa^+/–) would not be adequate to protect heterozygous mice against exaggerated cardiac hypertrophy and remodeling after pressure-overload stress. Nppa^+/+, Nppa^+/–, and Nppa^–/– mice were subjected to sham surgery or transverse aortic constriction and fed a basal salt diet. Heart weight varied inversely with Nppa gene load by 1 week after either surgery. Fractional shortening did not differ among genotypes at baseline and fell in Nppa^–/– mice only after transverse aortic constriction. There was a graded response in collagen deposition related to atrial natriuretic peptide (ANP) expression after either surgery. A robust interstitial and perivascular fibrosis was noted in Nppa^–/– and Nppa^+/– but not in Nppa^+/+ mice after transverse aortic constriction. Our findings are consistent with a growing body of evidence that ANP is an important modulator of cardiac hypertrophy and remodeling in response to hemodynamic stress. The observation that partial ANP deficiency results in exaggerated hypertrophy and remodeling after pressure overload suggests that genetic or environmental variation in ANP levels may play a role in the development of cardiac hypertrophy, remodeling, and failure in humans.

Key Words: atrial natriuretic factor • natriuretic peptides • receptors, atrial natriuretic factor • hypertrophy, cardiac • remodeling • extracellular matrix • collagen

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Recent studies suggest that atrial natriuretic factor (ANP) is an autocrine/paracrine modulator of cardiac hypertrophy and remodeling in response to pathologic stimuli.^1–10 Mice with homozygous deletion of the pro-ANP gene (Nppa^–/–) or the natriuretic peptide receptor-A gene (Npr1^–/–) exhibit cardiac hypertrophy under resting conditions^3,5,11–13 and develop exaggerated hypertrophy after volume or pressure overload.^6,12,13 Furthermore, these studies raise the question as to whether variation in ANP response to hemodynamic stress is an important mediator of cardiac hypertrophy and remodeling in human hypertension and heart failure. Although studies in Nppa^–/– mice have clearly demonstrated the adverse effect of ANP deletion on cardiac hypertrophy and remodeling, the effect of a modest ANP deficiency on the development of cardiac hypertrophy, remodeling, and failure remains unknown.

ANP-heterozygous mice (Nppa^+/–) have normal blood pressure on either a normal- (0.5% NaCl) or an intermediate-salt (2% NaCl) diet,^6,14 in contrast to the hypertension observed in Nppa^–/– mice under these conditions.¹¹ On a very-high-salt (8% NaCl) diet, however, Nppa^+/– mice develop hypertension.⁶ The cardiac phenotype of the heterozygous ANP-knockout has not been rigorously studied under either basal or stress conditions. However, in their original report of this model, John et al⁶ did not find a significant difference in cardiac weight between Nppa^+/+ and Nppa^+/– mice. The relatively normal cardiac phenotype in the heterozygous ANP-knockout might indicate that the quantity of ANP is not critical under nonstressful conditions. In a different murine model, we demonstrated that variation in angiotensin-converting enzyme levels does not importantly affect either angiotensin II levels or the hypertrophic response to volume overload.¹⁵ Thus, effects of the complete absence or pharmacological blockade of a gene product does not predict whether or not a modest variation in that gene product will have important effects on phenotype.

The effect of varying levels of endogenous ANP expression on cardiac structure and the development of heart failure is unknown and difficult to study in humans, owing to a confounding effect of increased ANP expression with worsening severity of failure. The Nppa^+/– mouse provides an ideal model to study the effect of a modest reduction in ANP expression on cardiac remodeling and function in response to hemodynamic stress. We hypothesized that ANP-heterozygous mice would demonstrate a normal cardiac phenotype under nonstressful conditions but an exaggerated cardiac hypertrophy and remodeling in response to pressure-overload stress.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Animal Preparation
Heterozygous Nppa^+/– mice were obtained by breeding female Nppa^+/+ and male Nppa^–/– mice in our resident colonies. Wild-type Nppa^+/+ mice of the C57BL/6 strain and Nppa^–/– mice were originally generated by Dr Oliver Smithies.⁶ Genotypes were identified by polymerase chain reaction.¹⁶ Mice were housed 3 or 4 per cage; maintained at constant humidity (60±5%), temperature (24±1°C), and light cycle (6 AM to 6 PM); and fed a standard diet (0.55% NaCl, Harlan-Teklad). All protocols were approved by the Institutional Animal Care and Use Committee at the University of Alabama at Birmingham and were consistent with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 96-01, revised 1996).

Surgical Procedure
Male Nppa^+/+, Nppa^+/–, and Nppa^–/– mice, 9 to 12 weeks of age, were anesthetized with an intraperitoneally administered mixture of ketamine (8 mg/100 g) and xylazine (1.2 mg/100 g), and transverse aortic constriction (TAC) was performed as described previously.¹³ Pressure gradients across the TAC were similar among genotypes (53±6.5 mm Hg in Nppa^+/+ and 55±6.8 mm Hg in Nppa^–/– mice).¹³ Sham-operated mice served as controls.

Echocardiographic Study
One week after TAC or sham surgery, echocardiography was performed as previously described^11,12 with a 6- to 15-MHz transducer (Philips) and a commercially available ultrasound system (Phillips Sonos 5500). Left ventricular (LV) end-diastolic dimension (EDD), LV end-systolic dimension (ESD), and septal (interventricular septal [IVS[) and posterior wall (PW) diastolic thicknesses were measured by 2D-guided M-mode echocardiography from the parasternal long-axis view. Wall thickness was calculated as the average of IVS and PW. Fractional shortening (FS) was calculated by the formula (LVEDD–LVESD)/LVEDD. A single examiner, blinded to genotype and treatment, performed all studies.

Plasma ANP
Blood (0.5 mL) was collected via retro-ocular approach from conscious mice the day after the echocardiographic study. ANP measurement was performed as previously described with the use of radioimmunoassay kits (Peninsula Laboratories).¹⁷

Tissue Collection
Mice were humanely killed after blood collection by cervical dislocation. Hearts were removed, and the LV, right ventricle (RV), and atria were weighed. The LV was divided into 2 portions: the apical portion was fixed with 4% paraformaldehyde, embedded in paraffin, and sectioned for histologic analysis; the basal portion was immediately frozen in LN₂ for RNA isolation. Lung, kidney, brain, liver, and spleen were also weighed.

Collagen Volume
LV myocardial collagen (interstitial and perivascular) volume, at the level below the mitral valve, was measured in picrosirius red (0.1%)-stained cross sections on a microscopic system with a green (540-nm) filter to enhance contrast for computer imaging analysis (Image-1 Software). Only collagen fibers appear green; green regions are counted by the aforementioned software and are given as a percentage of the total area per field. A minimum of 8 randomly selected images were counted from each LV. A single examiner, blinded to the experimental group, performed all histologic analyses.

Northern Blot Analysis
Northern blot analysis was performed as described previously¹³ with ³²P-labeled selective cDNA probes for ANP (generated in our laboratory by reverse transcription-polymerase chain reaction with mouse heart RNA as the template¹⁸). 18S rRNA was used as a control to account for variation in RNA loading.

Statistical Analysis
Results are expressed as mean±SEM. Tissue weights and echocardiographic measurements were normalized by ANCOVA with body weight as the covariate.^19,20 Our primary statistical test was ANOVA, 1-way ANOVA to evaluate the differences in mean values due to main effects (genotype or TAC), and 2-way ANOVA to test their interactions. P<0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Plasma ANP and Cardiac ANP mRNA Expression
There was no difference in plasma ANP level or LV ANP mRNA expression between sham Nppa^+/– and Nppa^+/+ mice (Figure 1). Nppa^–/– mice had disrupted pro-ANP mRNA,¹⁷ and plasma ANP and LV ANP mRNA levels were undetectable. TAC increased plasma ANP and LV ANP mRNA levels in Nppa^+/– and Nppa^+/+ mice compared with sham controls. There was a genotypic effect on ANP response to TAC: Nppa^+/– mice had less robust responses to TAC than did Nppa^+/+ mice (2-way ANOVA, P<0.05).

View larger version (26K): [in this window] [in a new window]   Figure 1. A, Plasma ANP levels of Nppa+/+, Nppa+/–, and Nppa–/– mice after TAC or sham surgery and B, cardiac ANP mRNA expression of Nppa+/+, Nppa+/–, and Nppa–/– mice after TAC or sham surgery. GxTAC indicates genotype by TAC interactions. Results are mean±SEM, where n=number of mice. *P<0.05 vs respective sham mice; P<0.05 vs respective Nppa+/+ mice; P<0.05 vs respective Nppa+/– mice. Other abbreviations are as defined in text.

Tissue Weight
Both genotype and TAC affected whole-heart, LV, and RV weight, and there was an interaction between these 2 variables (Table 1). Whole-heart and LV weight followed ANP gene expression in Nppa^–/– versus both Nppa± and Nppa^+/+ mice, as in Nppa^+/– and Nppa^+/+ mice, after sham surgery. Whole-heart, LV, and RV weight differed among all 3 genotypes in a graded fashion (Nppa^–/–>Nppa^+/–>Nppa^+/+) after TAC.

View this table: [in this window] [in a new window]   TABLE 1. Normalized Heart and Tissue Weights of Nppa+/+, Nppa+/–, and Nppa–/– Mice 1 Week After TAC or Sham Surgery

Echocardiography
Normalized echocardiographic measurements are shown in Table 2. LVEDD was increased by TAC and by decreasing the number of ANP genes. Pairwise multiple comparison revealed that LVEDD did not differ among the 3 genotypes after sham surgery. After TAC, LVEDD was greater in Nppa^–/– versus Nppa^+/– and in Nppa^–/– versus Nppa^+/+ mice but did not differ between Nppa^+/– and Nppa^+/+ mice. LVFS did not differ among the 3 genotypes after sham surgery and was reduced only in Nppa^–/– mice subjected to TAC.

View this table: [in this window] [in a new window]   TABLE 2. Normalized Echocardiographic Measurements of Nppa+/+, Nppa+/–, andNppa–/– Mice 1 Week After TAC or Sham Surgery

Collagen Volume
Collagen volume differed significantly among the 3 genotypes after sham surgery (Nppa^+/+, 0.2±0.0%; Nppa^+/–, 1.1±0.2%; and Nppa^–/–, 3.5±0.2%; P<0.05, 1-way ANOVA) and after TAC (Nppa^+/+, 0.1±0.0%; Nppa^+/–, 6.4±1.3%; and Nppa^–/–, 24.3±5.9%; P<0.01, 1-way ANOVA). Collagen deposition occurred predominantly in the interstitium and perivascular area after TAC and was inversely related to ANP gene load (Figure 2 A and 2B). There was robust interstitial and perivascular fibrosis in TAC-Nppa^–/– mice and a significant but less severe response in TAC-Nppa^+/– mice (2-way ANOVA, P<0.01, interaction of genotypexTAC). Collagen deposition increased by 6-fold in TAC-Nppa^–/– and TAC-Nppa^+/– mice when compared with their sham controls but did not differ between sham and TAC-Nppa^+/+ mice.

View larger version (85K): [in this window] [in a new window]   Figure 2. A, Picrosirius red-stained cross sections and B, perivascular areas of the LV at the level below the mitral valve of Nppa+/+, Nppa+/–, and Nppa–/– mice after TAC or sham surgery. Abbreviations are as defined in text.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major finding of this study is that the mouse heterozygous for ANP expression displays an intermediate phenotype between that of the Nppa^+/+ and Nppa^–/– mouse both at baseline and in response to hemodynamic stress. Cardiac hypertrophy and remodeling were exaggerated after pressure-overload stress in a graded response related to ANP expression, with even partial ANP deficiency resulting in adverse cardiac remodeling under hemodynamic stress. Our results emphasize the importance of ANP as a modulator of cardiac growth and collagen content under both basal and stressful conditions and suggest that the gene encoding ANP is a good candidate for investigation with regard to the development of cardiac hypertrophy, remodeling, and failure in humans.

Previous studies have documented that the complete absence of ANP or its receptor results in the development of salt-sensitive hypertension, cardiac hypertrophy, and remodeling.^3,5,6,21,22 Partial ANP deficiency does not affect blood pressure on a normal-salt diet⁶ but has not been rigorously studied with regard to cardiac phenotype. John et al⁶ reported cardiac weight only for Nppa^+/+ and Nppa^+/– mice fed 2% NaCl and found a statistically nonsignificant increase in the Nppa^+/– genotype, similar in magnitude to that observed in sham-operated animals in the current study. We also observed a modest increase in both collagen volume and heart weight in the heterozygotes versus wild types under basal conditions, despite apparently similar ANP levels. Because of limitations in the sensitivity (10 to 20 pg/mL of plasma) of the radioimmunoassay for ANP and Northern blot analysis of ANP mRNA, it is possible that there are small (<20%) differences in these parameters between Nppa^+/– and Nppa^+/+ mice that were undetectable by our methods. Clearly, major differences in ANP levels between Nppa^+/– and Nppa^+/+ were manifested only under stress conditions. It is unlikely that higher blood pressure explains these increases in heart weight and collagen volume in heterozygous versus wild-type mice, because previous reports have documented no difference in blood pressure between Nppa^+/+ and Nppa^+/– mice on either a normal- (0.5%) or an intermediate- (2.0% NaCl) salt diet.^6,14 In addition, correction of hypertension in Nppa^–/– mice by a very-low-salt diet (0.05% NaCl) does not prevent cardiac hypertrophy, either at baseline or in response to hemodynamic stress, suggesting that alternative mechanisms are operative in ANP-induced hypertrophy and fibrosis.¹¹

In the current study, partial ANP deficiency clearly resulted in excess cardiac hypertrophy and remodeling in response to hemodynamic stress compared with wild-type mice. This was accompanied by a 6-fold increase in collagen in TAC-Nppa^+/– and TAC-Nppa^–/– versus the respective sham-operated mice compared with no change in collagen volume in Nppa^+/+ mice after TAC. Importantly, whereas collagen volume increased after TAC in Nppa^+/– relative to sham and to TAC-Nppa^+/+ mice, it was still substantially less than that seen in TAC-Nppa^–/– mice. Consistent with those findings, the presence of 1 copy of the ANP gene was sufficient to protect against the development of LV dysfunction compared with mice with a complete absence of ANP. In contrast to ANP, B-type natriuretic peptide (BNP) appears not to modulate cardiac enlargement. BNP^–/– mice do not develop cardiac hypertrophy²³; circulating BNP is not increased in Nppa^–/– mice²⁴; and BNP is unable to compensate for the lack of ANP in Nppa^–/– mice under stress conditions.^13,16,24 These findings suggest that ANP deficiency alone is sufficient to generate cardiac hypertrophy/remodeling, particularly under conditions of hemodynamic stress. Our findings are consistent with a growing body of evidence that remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy, leading to cardiac dysfunction and failure,^25–29 and underscore the importance of ANP as a modulator of that interstitial remodeling.^12,13

Perspectives
The observation in the current study that cardiac weight and collagen content vary with ANP gene load both at baseline and after 1 week of pressure-overload hemodynamic stress underscores the critical role of ANP in modulating cardiac growth and structure under both physiologic and pathophysiologic conditions. We chose heterozygous ANP-knockout mice for the current study because humans are more likely to have partial rather than an absolute deficiency of ANP. Both environmental and genetic variations in ANP have been described in humans. Blunted secretion of ANP has been observed in black salt-sensitive hypertensives in response to high salt intake,³⁰ and a polymorphism of the ANP gene has been observed more frequently in black salt-sensitive hypertensives compared with normotensives or white hypertensives.^31–33 Obese individuals demonstrate decreased levels of both ANP and BNP, possibly related to more rapid clearance by adipocyte NPR-C receptors.³⁴ Our findings suggest that these observed variations in ANP levels maybe a fruitful area for study with regard to the development of cardiac hypertrophy, remodeling, and failure in response to hemodynamic stress in humans.

	Acknowledgments

 
This work was supported in part by National Heart, Lung, and Blood Institute grants HL07457 and HL44195 and by Southeast American Heart Association Grant-in-Aid No. 1637308.

Received July 10, 2004; first decision August 1, 2004; accepted September 1, 2004.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Klinger JR, Petit RD, Curtin LA, Warburton RR, Wrenn DS, Steinhelper ME, Field LJ, Hill NS. Cardiopulmonary responses to chronic hypoxia in transgenic mice that overexpress ANP. J Appl Physiol. 1993; 75: 198–205.[Abstract/Free Full Text]

2. Barbee RW, Perry BD, Re RN, Murgo JP, Field LJ. Hemodynamics in transgenic mice with overexpression of atrial natriuretic peptide. Circ Res. 1994; 74: 747–751.[Abstract/Free Full Text]

3. Oliver PM, Fox JE, Kim R, Rockman HA, Kim KS, Reddick RL, Pandey KU, Milgram SL, Smithies O, Maede N. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A. 1997; 94: 14730–14735.[Abstract/Free Full Text]

4. Kishimoto I, Rossi K, Garbers DL. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular hypertrophy. Proc Natl Acad Sci U S A. 2001; 98: 2703–2706.[Abstract/Free Full Text]

5. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, Maeda N. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest. 2001; 107: 975–984.[Medline] [Order article via Infotrieve]

6. John SWM, Krege JH, Oliver PM, Hageman JR, Hodgin JB, Pang SC, Flynn TG, Smithies O. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science. 1995; 267: 679–681.[Abstract/Free Full Text]

7. Cao L, Gardner DG. Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. Hypertension. 1995; 25: 227–234.[Abstract/Free Full Text]

8. Calderone A, Thaik CM, Takahashi N, Chang DLF, Colucci WS. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest. 1998; 101: 812–818.[Medline] [Order article via Infotrieve]

9. Horio T, Nishikimi T, Toshihara F, Matsuo H, Takishita S, Kangawa K. Inhibitory regulation of hypertrophy by endogenous atrial natriuretic peptide in cultured cardiac myocytes. Hypertension. 2000; 35: 19–24.[Abstract/Free Full Text]

10. Klinger JR, Warburton RR, Pietras L, Oliver P, Fox J, Smithies O, Hill NS. Targeted disruption of the gene for natriuretic peptide receptor-A worsens hypoxia-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2002; 282: H58–H65.[Abstract/Free Full Text]

11. Feng JA, Perry GJ, Mori T, Hayashi T, Oparil S, Chen YF. Pressure-independent enhancement of cardiac hypertrophy in atrial natriuretic peptide-deficient mice. Clin Exp Pharmacol Physiol. 2003; 30: 343–349.[CrossRef][Medline] [Order article via Infotrieve]

12. Mori T, Chen YF, Feng JA, Hiyashi T, Oparil S, Perry GJ. Volume overload results in exaggerated cardiac hypertrophy in the atrial natriuretic peptide knockout mouse. Cardiovasc Res. 2004; 61: 771–779.[Abstract/Free Full Text]

13. Wang D, Oparil S, Feng JA, Li P, Perry G, Chen LB, Dai M, John SWM, Chen YF. Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension. 2003; 42: 88–92.[Abstract/Free Full Text]

14. John SWM, Veress AT, Honrath U, Chong CK, Peng L, Smithies O, Sonnenberg H. Blood pressure and fluid-electrolyte balance in mice with reduced or absent ANP. Am J Physiol. 1996; 271: R109–R114.[Medline] [Order article via Infotrieve]

15. Perry GJ, Mori T, Wei CC, Xu XY, Chen YF, Oparil S, Lucchesi P, Dell’Italia LJ. Genetic variation in angiotensin-converting enzyme does not prevent development of cardiac hypertrophy or upregulation of angiotensin II in response to aortocaval fistula. Circulation. 2001; 103: 1012–1016.[Abstract/Free Full Text]

16. Sun JZ, Chen SJ, Li G, Chen YF. Hypoxia reduces atrial natriuretic peptide clearance receptor gene expression in ANP knockout mice. Am J Physiol Lung Cell Mol Physiol. 2000; 279: L511–L519.[Abstract/Free Full Text]

17. Sun JZ, Chen SJ, Majid-Hassen E, Oparil S, Chen YF. Dietary salt-supplementation selectively downregulates NPR-C receptor expression in kidney independent of ANP. Am J Physiol. 2002; 282: F220–F227.

18. Li H, Oparil S, Meng QC, Elton T, Chen YF. Selective downregulation of ANP-clearance receptor expression in lung of rats adapted to hypoxia. Am J Physiol. 1995; 268: L328–L335.[Medline] [Order article via Infotrieve]

19. Packard GC, Boardman TJ. The misuse of ratios to scale physiological data that vary allometrically with body size. In: Feder ME, Bennett AF, Burggren WW, Huey RB, eds. New Directions in Ecological Physiology. Cambridge, UK: Cambridge University Press; 1987: 216–239.

20. Packard GC, Boardman TJ. The misuse of ratios, indices, and percentages in ecophysiological research. Physiol Zool. 1988; 61: 1–9.

21. Molketin JD. A friend within the heart: natriuretic peptide receptor signaling. J Clin Invest. 2003; 111: 1275–1277.[CrossRef][Medline] [Order article via Infotrieve]

22. Holtwick R, van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, Kuhn M. Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest. 2003; 111: 1399–1407.[CrossRef][Medline] [Order article via Infotrieve]

23. Ogawa Y, Tamura N, Chusho H, Nakao K. Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart. Can J Physiol Pharmacol. 2001; 79: 723–729.[CrossRef][Medline] [Order article via Infotrieve]

24. Tse MY, Watson JD, Sarda IR, Flynn TG, Pang SC. Expression of B-type natriuretic peptide in atrial natriuretic peptide gene disrupted mice. Mol Cell Biochem. 2001; 219: 99–105.[CrossRef][Medline] [Order article via Infotrieve]

25. Spinale FG. Matrix metalloproteinases, regulation and dysregulation in the failing heart. Circ Res. 2002; 90: 520–530.[Abstract/Free Full Text]

26. Wilson EM, Spinale FG. Myocardial remodeling and matrix metalloproteinase in heart failure: turmoil within the interstitium. Ann Med. 2001; 33: 623–634.[Medline] [Order article via Infotrieve]

27. Li YY, McTiernan CF, Feldman AM. Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinase and their regulators in cardiac matrix remodeling. Cardiovasc Res. 2000; 46: 214–224.[Abstract/Free Full Text]

28. Manabe I, Shindo T, Nagia R. Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy. Circ Res. 2002; 91: 1103–1113.[Abstract/Free Full Text]

29. Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, Bauer EP, Klövekorn WP, Schaper J. Progression from decompensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003; 107: 984–991.[Abstract/Free Full Text]

30. Campese VM, Tawadrous M, Bigazzi R, Bianchi S, Mann AS, Oparil S, Raij L. Salt intake and plasma atrial natriuretic peptide and nitric oxide in hypertension. Hypertension. 1996; 28: 335–340.[Abstract/Free Full Text]

31. Rutledge DR, Sun Y, Ross EA. Polymorphisms within the atrial natriuretic peptide gene in essential hypertension. J Hypertens. 1995; 13: 953–955.[CrossRef][Medline] [Order article via Infotrieve]

32. Beige J, Ringel J, Hohwnbleicher H, Rubattu S, Kreutz R, Sharma AM. Hpall-polymorphism of the atrial natriuretic peptide gene and essential hypertension in whites. Am J Hypertens. 1997; 10: 1316–1318.[CrossRef][Medline] [Order article via Infotrieve]

33. Nakayama T, Soma M, Takahashi Y, Rehemudula D, Kanmatsuse K, Furuya K. Functional deletion mutation of the 5'-flanking region of type A human natriuretic peptide receptor gene and association with essential hypertension and left ventricular hypertrophy in the Japanese. Circ Res. 2000; 86: 841–845.[Abstract/Free Full Text]

34. Sarzani R, Dessi-Fulgheri P, Salvi F, Serenelli M, Spagnolo D, Cola D, Pupita M, Giantomassi L, Rappelli A. A novel promoter variant of the natriuretic peptide clearance receptor gene is associated with lower atrial natriuretic peptide and higher blood pressure in obese hypertensives. J Hypertens. 1999; 17: 1301–1305.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				J. A. Lucas, Y. Zhang, P. Li, K. Gong, A. P. Miller, E. Hassan, F. Hage, D. Xing, B. Wells, S. Oparil, et al. Inhibition of transforming growth factor-{beta} signaling induces left ventricular dilation and dysfunction in the pressure-overloaded heart Am J Physiol Heart Circ Physiol, February 1, 2010; 298(2): H424 - H432. [Abstract] [Full Text] [PDF]

				H H Chen, F L Martin, R J Gibbons, J A Schirger, R S Wright, R M Schears, M M Redfield, R D Simari, A Lerman, A Cataliotti, et al. Low-dose nesiritide in human anterior myocardial infarction suppresses aldosterone and preserves ventricular function and structure: a proof of concept study Heart, August 15, 2009; 95(16): 1315 - 1319. [Abstract] [Full Text] [PDF]

				S. Kasama, M. Furuya, T. Toyama, S. Ichikawa, and M. Kurabayashi Effect of atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction Eur. Heart J., June 2, 2008; 29(12): 1485 - 1494. [Abstract] [Full Text] [PDF]

				I. L.O. Buxton and D. Duan Cyclic GMP/Protein Kinase G Phosphorylation of Smad3 Blocks Transforming Growth Factor-{beta}-Induced Nuclear Smad Translocation: A Key Antifibrogenic Mechanism of Atrial Natriuretic Peptide Circ. Res., February 1, 2008; 102(2): 151 - 153. [Full Text] [PDF]

				P. Li, D. Wang, J. Lucas, S. Oparil, D. Xing, X. Cao, L. Novak, M. B. Renfrow, and Y.-F. Chen Atrial Natriuretic Peptide Inhibits Transforming Growth Factor {beta}-Induced Smad Signaling and Myofibroblast Transformation in Mouse Cardiac Fibroblasts Circ. Res., February 1, 2008; 102(2): 185 - 192. [Abstract] [Full Text] [PDF]

				G. Casaclang-Verzosa, B. J. Gersh, and T. S.M. Tsang Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J. Am. Coll. Cardiol., January 1, 2008; 51(1): 1 - 11. [Abstract] [Full Text] [PDF]

				D. B. Murray, J. D. Gardner, S. P. Levick, G. L. Brower, L. G. Morgan, and J. S. Janicki Response of cardiac mast cells to atrial natriuretic peptide Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1216 - H1222. [Abstract] [Full Text] [PDF]

				S J. Sangaralingham, M Y. Tse, and S. C Pang Estrogen protects against the development of salt-induced cardiac hypertrophy in heterozygous proANP gene-disrupted mice J. Endocrinol., July 1, 2007; 194(1): 143 - 152. [Abstract] [Full Text] [PDF]

				A. M. Richards Natriuretic Peptides: Update on Peptide Release, Bioactivity, and Clinical Use Hypertension, July 1, 2007; 50(1): 25 - 30. [Full Text] [PDF]

				V. Franco and S. Oparil Is There a New Treatment for Hypertensive Disease in the Horizon?: Role of Soluble Guanylate Cyclase Hypertension, November 1, 2006; 48(5): 822 - 823. [Full Text] [PDF]

				A. Maguy, T. E. Hebert, and S. Nattel Involvement of lipid rafts and caveolae in cardiac ion channel function Cardiovasc Res, March 1, 2006; 69(4): 798 - 807. [Abstract] [Full Text] [PDF]

				T. Nishikimi, N. Maeda, and H. Matsuoka The role of natriuretic peptides in cardioprotection Cardiovasc Res, February 1, 2006; 69(2): 318 - 328. [Abstract] [Full Text] [PDF]

				G. W. Booz Putting the Brakes on Cardiac Hypertrophy: Exploiting the NO-cGMP Counter-Regulatory System Hypertension, March 1, 2005; 45(3): 341 - 346. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 44/5/746    most recent 01.HYP.0000144801.09557.4cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Franco, V. Articles by Perry, G. Search for Related Content PubMed PubMed Citation Articles by Franco, V. Articles by Perry, G. Related Collections Structure Contractile function Other heart failure Remodeling Other hypertension Heart failure - basic studies Physiological and pathological control of gene expression