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Gene Review

Nppa  -  natriuretic peptide type A

Mus musculus

Synonyms: ANP, Anf, Natriuretic peptides A, Pnd, Prepronatriodilatin, ...
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Disease relevance of Nppa

  • A 0.05% NaCl diet from weaning normalized BP, but did not prevent exaggerated cardiac enlargement and LV hypertrophy following ACF in Nppa(-/-) mice [1].
  • METHODS: Male homozygous ANP deficient (Nppa(-/-)) and wildtype (Nppa(+/+)) male mice maintained on either a normal salt (0.55% NaCl) or low salt (0.05% NaCl) diet from weaning were studied after 2 weeks of volume overload from an aorto-caval fistula (ACF) [1].
  • 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 [2].
  • A robust interstitial and perivascular fibrosis was noted in Nppa-/- and Nppa+/- but not in Nppa+/+ mice after transverse aortic constriction [2].
  • Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease [3].

Psychiatry related information on Nppa


High impact information on Nppa

  • We discovered that a family of transcriptional coactivators, called CAMTAs, promotes cardiomyocyte hypertrophy and activates the ANF gene, at least in part, by associating with the cardiac homeodomain protein Nkx2-5 [6].
  • In an effort to discover regulators of cardiac hypertrophy, we performed a eukaryotic expression screen for activators of the atrial natriuretic factor (ANF) gene, a cardiac-specific marker of hypertrophic signaling [6].
  • Aldosterone and ANP concentrations are not affected by the genotype [7].
  • A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor [8].
  • One of the earliest events following binding of ANP to receptors on target cells is an increase in cyclic GMP concentration, indicating that this nucleotide might act as a mediator of the physiological effects of the hormone [8].

Chemical compound and disease context of Nppa


Biological context of Nppa


Anatomical context of Nppa

  • Increased myocyte diameter paralleled increased echo LV wall thickness following ACF in Nppa(+/+) but not Nppa(-/-) mice fed with 0.55% NaCl, indicating that an alternate mechanism contributed to increased wall thickness in Nppa(-/-) mice [1].
  • Expression of Nppa is an early and specific marker for the differentiating working myocardium of the atria and ventricles of the developing heart [14].
  • In such heart, left ventricle (LV)-specific ANF gene was induced [17].
  • Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co-transfection of Nkx2.5 in the C3H10T1/2 embryonic fibroblast cell line [18].
  • CNP mRNA was expressed abundantly in fetal mouse tibias, where no significant amounts of ANP and BNP mRNAs were detected [19].

Associations of Nppa with chemical compounds

  • Corin is a cardiac transmembrane serine protease that has been shown to process pro-ANP in vitro, but its physiological importance had not been established [3].
  • RESULTS: cGMP accumulation after stimulation by atrial NP (ANP) or C-type NP (CNP) was markedly inhibited in D-NOD cells irrespective of the glucose concentration (6 or 20 mM) in the culture medium [20].
  • Reduction of nitrite accumulation by ANP was highest when added simultaneously with LPS and abolished when added 12 h after LPS stimulation [21].
  • (3) The potency of ANP and CNP in aortae from WT animals was increased in the presence of the NOS inhibitor, N(G)-nitro-L-arginine (3 x 10(-4) M) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (5 x 10(-6) M) [22].
  • (5) Responses to acetylcholine in aortae from WT mice (dependent on the release of endothelium-derived NO) were significantly reduced following pretreatment of tissues with GTN (3 x 10(-5) M, 30 min) and ANP (10(-7) M, 30 min) [22].

Physical interactions of Nppa

  • In vivo inactivation of a T-box factor (TBE)- or NK2-homeobox factor binding element (NKE) within the ANF fragment removed the repression in the AVC without affecting its chamber activity [23].
  • The membrane-bound form of guanylate cyclase/atrial natriuretic factor receptor (GC/ANF-R) is a 135 kDa transmembrane glycoprotein which binds ANF with high affinity [24].

Regulatory relationships of Nppa


Other interactions of Nppa

  • Coincident with the reduction in myocyte size, both ANP mRNA and ANP content were significantly reduced by overexpression of GC-A, and this reduction was independent of genotype [29].
  • These studies have determined that the Pctr2 locus resides in either a 500-kb interval proximal to Nppa, or in a 1- to 2-centiMorgan (cM) interval distal to Nppa [30].
  • Strikingly, reduced levels of Anf expression were also observed in embryonic day 9.5 Carp-Lbh transgenic mice [31].
  • CNP increased the cGMP production much more potently than ANP, thereby resulting in an increase in the total longitudinal bone length [19].
  • We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity [18].

Analytical, diagnostic and therapeutic context of Nppa

  • Fractional shortening did not differ among genotypes at baseline and fell in Nppa-/- mice only after transverse aortic constriction [2].
  • We used in situ hybridization to identify the sites of gene expression of ANP, BNP, and CNP during development in mouse embryos at daily intervals from midgestation [32].
  • Since the original discovery of atrial natriuretic peptide (ANP) more than two decades ago, the application of gene targeting technology in mice has provided new insights into the diverse physiological functions of natriuretic peptides and their membrane guanylyl cyclase (GC) receptors [33].
  • Northern Blot analysis shows the ANP-/- mice has a 40% reduction of BNP mRNA level in the atrium and a 5-fold increase in the ventricle as compared with that of the ANP+/+ mouse [34].
  • The coexpression of the natriuretic peptides ANP, BNP and CNP as well as their differential regulation in mouse macrophages was demonstrated by quantitative PCR, HPLC analysis, and specific radioimmunoassays [35].


  1. Volume overload results in exaggerated cardiac hypertrophy in the atrial natriuretic peptide knockout mouse. Mori, T., Chen, Y.F., Feng, J.A., Hayashi, T., Oparil, S., Perry, G.J. Cardiovasc. Res. (2004) [Pubmed]
  2. Atrial natriuretic peptide dose-dependently inhibits pressure overload-induced cardiac remodeling. Franco, V., Chen, Y.F., Oparil, S., Feng, J.A., Wang, D., Hage, F., Perry, G. Hypertension (2004) [Pubmed]
  3. Hypertension in mice lacking the proatrial natriuretic peptide convertase corin. Chan, J.C., Knudson, O., Wu, F., Morser, J., Dole, W.P., Wu, Q. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. The effect of water deprivation on the expression of atrial natriuretic peptide and its receptors in the spinifex hopping mouse, Notomys alexis. Heimeier, R.A., Davis, B.J., Donald, J.A. Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. (2002) [Pubmed]
  5. Effects of atrial natriuretic peptide on phagocytosis and respiratory burst in murine macrophages. Vollmar, A.M., Förster, R., Schulz, R. Eur. J. Pharmacol. (1997) [Pubmed]
  6. The Transcriptional Coactivator CAMTA2 Stimulates Cardiac Growth by Opposing Class II Histone Deacetylases. Song, K., Backs, J., McAnally, J., Qi, X., Gerard, R.D., Richardson, J.A., Hill, J.A., Bassel-Duby, R., Olson, E.N. Cell (2006) [Pubmed]
  7. Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Lopez, M.J., Wong, S.K., Kishimoto, I., Dubois, S., Mach, V., Friesen, J., Garbers, D.L., Beuve, A. Nature (1995) [Pubmed]
  8. A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor. Chinkers, M., Garbers, D.L., Chang, M.S., Lowe, D.G., Chin, H.M., Goeddel, D.V., Schulz, S. Nature (1989) [Pubmed]
  9. Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan. Holtwick, R., Baba, H.A., Ehler, E., Risse, D., Vobeta, M., Gehrmann, J., Pierkes, M., Kuhn, M. J. Cardiovasc. Pharmacol. (2002) [Pubmed]
  10. Vasodilatory action of endogenous atrial natriuretic factor in a rat model of chronic heart failure as determined by monoclonal ANF antibody. Drexler, H., Hirth, C., Stasch, H.P., Lu, W., Neuser, D., Just, H. Circ. Res. (1990) [Pubmed]
  11. Convergence of protein kinase C and JAK-STAT signaling on transcription factor GATA-4. Wang, J., Paradis, P., Aries, A., Komati, H., Lefebvre, C., Wang, H., Nemer, M. Mol. Cell. Biol. (2005) [Pubmed]
  12. Inhibitory regulation of hypertrophy by endogenous atrial natriuretic peptide in cultured cardiac myocytes. Horio, T., Nishikimi, T., Yoshihara, F., Matsuo, H., Takishita, S., Kangawa, K. Hypertension (2000) [Pubmed]
  13. Characterization of atrial-natriuretic-factor-receptor-coupled membrane guanylate cyclase from rat and mouse testes. Marala, R.B., Sharma, R.K. Biochem. J. (1988) [Pubmed]
  14. Expression and regulation of the atrial natriuretic factor encoding gene Nppa during development and disease. Houweling, A.C., van Borren, M.M., Moorman, A.F., Christoffels, V.M. Cardiovasc. Res. (2005) [Pubmed]
  15. Comparative analysis of the natriuretic peptide precursor gene cluster in vertebrates reveals loss of ANF and retention of CNP-3 in chicken. Houweling, A.C., Somi, S., Massink, M.P., Groenen, M.A., Moorman, A.F., Christoffels, V.M. Dev. Dyn. (2005) [Pubmed]
  16. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Matsukawa, N., Grzesik, W.J., Takahashi, N., Pandey, K.N., Pang, S., Yamauchi, M., Smithies, O. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  17. Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis. Takeuchi, J.K., Ohgi, M., Koshiba-Takeuchi, K., Shiratori, H., Sakaki, I., Ogura, K., Saijoh, Y., Ogura, T. Development (2003) [Pubmed]
  18. PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5. Ganga, M., Espinoza, H.M., Cox, C.J., Morton, L., Hjalt, T.A., Lee, Y., Amendt, B.A. J. Biol. Chem. (2003) [Pubmed]
  19. Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. Yasoda, A., Ogawa, Y., Suda, M., Tamura, N., Mori, K., Sakuma, Y., Chusho, H., Shiota, K., Tanaka, K., Nakao, K. J. Biol. Chem. (1998) [Pubmed]
  20. Mesangial cells from diabetic NOD mice constitutively express increased density of atrial natriuretic peptide C receptors. Ardaillou, N., Placier, S., Striker, L., Striker, G., Ardaillou, R. Kidney Int. (1999) [Pubmed]
  21. Effects of different natriuretic peptides on nitric oxide synthesis in macrophages. Kiemer, A.K., Vollmar, A.M. Endocrinology (1997) [Pubmed]
  22. Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling. Madhani, M., Scotland, R.S., MacAllister, R.J., Hobbs, A.J. Br. J. Pharmacol. (2003) [Pubmed]
  23. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Habets, P.E., Moorman, A.F., Clout, D.E., van Roon, M.A., Lingbeek, M., van Lohuizen, M., Campione, M., Christoffels, V.M. Genes Dev. (2002) [Pubmed]
  24. Expression of extracellular ligand-binding domain of murine guanylate cyclase/atrial natriuretic factor receptor cDNA in Escherichia coli. Pandey, K.N., Kanungo, J. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  25. Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide. Goy, M.F., Oliver, P.M., Purdy, K.E., Knowles, J.W., Fox, J.E., Mohler, P.J., Qian, X., Smithies, O., Maeda, N. Biochem. J. (2001) [Pubmed]
  26. The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart. Hoogaars, W.M., Tessari, A., Moorman, A.F., de Boer, P.A., Hagoort, J., Soufan, A.T., Campione, M., Christoffels, V.M. Cardiovasc. Res. (2004) [Pubmed]
  27. Calcineurin-nuclear factor of activated T cells pathway-dependent cardiac remodeling in mice deficient in guanylyl cyclase A, a receptor for atrial and brain natriuretic peptides. Tokudome, T., Horio, T., Kishimoto, I., Soeki, T., Mori, K., Kawano, Y., Kohno, M., Garbers, D.L., Nakao, K., Kangawa, K. Circulation (2005) [Pubmed]
  28. Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes. Chandrasekar, B., Mummidi, S., Claycomb, W.C., Mestril, R., Nemer, M. J. Biol. Chem. (2005) [Pubmed]
  29. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Kishimoto, I., Rossi, K., Garbers, D.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  30. The plasmacytoma resistance gene, Pctr2, delays the onset of tumorigenesis and resides in the telomeric region of chromosome 4. Mock, B.A., Hartley, J., Le Tissier, P., Wax, J.S., Potter, M. Blood (1997) [Pubmed]
  31. Congenital heart disease reminiscent of partial trisomy 2p syndrome in mice transgenic for the transcription factor Lbh. Briegel, K.J., Baldwin, H.S., Epstein, J.A., Joyner, A.L. Development (2005) [Pubmed]
  32. The sites of gene expression of atrial, brain, and C-type natriuretic peptides in mouse fetal development: temporal changes in embryos and placenta. Cameron, V.A., Aitken, G.D., Ellmers, L.J., Kennedy, M.A., Espiner, E.A. Endocrinology (1996) [Pubmed]
  33. Cardiac and intestinal natriuretic peptides: insights from genetically modified mice. Kuhn, M. Peptides (2005) [Pubmed]
  34. Expression of B-type natriuretic peptide in atrial natriuretic peptide gene disrupted mice. Tse, M.Y., Watson, J.D., Sarda, I.R., Flynn, T.G., Pang, S.C. Mol. Cell. Biochem. (2001) [Pubmed]
  35. Expression and differential regulation of natriuretic peptides in mouse macrophages. Vollmar, A.M., Schulz, R. J. Clin. Invest. (1995) [Pubmed]
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