Elsevier

Peptides

Volume 26, Issue 6, June 2005, Pages 944-956
Peptides

Molecular regulation of the brain natriuretic peptide gene

https://doi.org/10.1016/j.peptides.2004.08.028Get rights and content

Abstract

After brain natriuretic peptide (BNP) was isolated in 1988, rapid progress was made in cloning its cDNA and gene, facilitating studies of tissue-specific expression and molecular regulation of gene expression. This review focuses on the molecular determinants of regulation of the rat and human BNP genes, including signaling pathways that impact on changes in gene expression and cis regulatory elements responsive to these signaling pathways. For both rat and human genes, elements in the proximal promoter (−124 to −80), including GATA, MCAT, and AP-1-like, have been shown to contribute to basal and inducible regulation. More distal elements in the human BNP gene respond to calcium signals (an NF-AT site at −927), thyroid hormone (a thyroid-responsive element at −1000), and mechanical stretch (shear stress-responsive elements at −652 and −162). Understanding how BNP is regulated by signaling molecules that are activated in the hypertrophied and ischemic heart should be useful in understanding the underlying pathology. This may lead to therapeutic strategies that prevent hypertrophy while allowing for the beneficial effects of BNP production.

Section snippets

Discovery and actions of BNP

B-type or brain natriuretic peptide (BNP) is a member of the natriuretic peptide family that has physiological effects similar to atrial natriuretic peptide (ANP), including diuretic, natriuretic, and vasorelaxant actions [43]. Like ANP, BNP is induced by pathophysiological conditions of the heart, including hypertrophy, myocardial infarction, and heart failure. Unlike ANP, BNP is constitutively synthesized by ventricular myocytes and is primarily a ventricular hormone. BNP levels have been

BNP cDNA and gene structure

BNP was originally isolated from the porcine brain [77]. Shortly thereafter, BNP cDNA was cloned from human [78], rat [36], and porcine [51], [69] atrial cDNA libraries. More recently, it has been cloned from other vertebrate species, including primitive fish [reviewed in [31], [80]].

Using cDNA probes, genomic clones were isolated from porcine and human genomic libraries [72], allowing for clarification of the exon and intron structure of BNP. The BNP gene has 3 exons and 2 introns, which has

Tissue-specific expression of BNP

Studies on tissue-specific expression of the ANP gene have shown high-level expression in the right atrium and virtually undetectable amounts of ANP mRNA and peptide in the left ventricle of healthy adult mammals. After the initial discovery of BNP, investigators examined the tissue distribution of the peptide and its mRNA. Localization of the peptide was difficult, as there were significant species-specific differences in the amino acid sequence of pro-BNP that prevented antibodies from

Basal and inducible regulation of the hBNP gene

After sequencing the 5′FS of the hBNP gene, the DNA sequence was scanned to identify potential regulatory elements that might be involved in activation of the gene. To define areas of the 5′FS that might be involved in positive or negative regulation of the hBNP gene, deletions were generated from position −1818 (relative to the transcription start site) to −40, subcloned upstream from a luciferase cDNA, and tested by transient transfection analysis. A combination of sequence and deletion

Basal and inducible regulation of the rat BNP (rBNP) gene

Basal and inducible regulation of the rat BNP promoter has been studied both in vitro and in vivo. Thuerauf et al. [84] isolated and sequenced 2500 base pairs of the rat 5′ FS (see Fig. 2 for proximal promoter elements). Extensive deletion analysis revealed a negative regulatory element between −535 and −398 [83]. As it happens, this region contains an NRSE located between −38 and −518. Elimination of an identical element in the hBNP promoter also upregulated basal promoter activity [41].

Post-transcriptional regulation of BNP mRNA

As indicated in Section 2, one of the clear differences between the ANP and BNP genes is the DNA sequence in the 5′FS and 3′UTR. AT-rich regions in the 3′UTR of genes make their mRNAs unstable. The AT-rich motif in cDNA is present in mRNA as an AU-rich region and has been documented in mRNA for protooncogenes, lymphokines, and cytokines [8], [73]. BNP mRNA was shown to decay more quickly than ANP mRNA after neonatal cardiac myocytes were treated with phorbol ester for 3 h, suggesting that the

Summary

Regulation of the hBNP promoter involves many signaling inputs, which target the proximal −124 to −80 region as well as more distal elements. As shown in Table 1, GATA, MCAT and AP-1-like regions are involved in basal regulation and are responsive to growth and pro-inflammatory signals. The proximal promoter is also responsive to signals generated by ischemic injury in vivo. More distal elements respond to mechanical stretch, the phosphatase calcineurin, and thyroid hormone. Like the hBNP

Acknowledgements

I would like to thank present and former technicians and fellows for their many meaningful contributions to our work over the years, including Jodi Sitkins, Guiyun Wu, M.D., Ding Wang, M.D., Ph.D., Quan He, Ph.D. and Mariela Mendez, Ph.D. Ms. Sitkins also helped with some of the figures. Our work was supported by National Institutes of Health grants HL 28982 and 03188.

References (88)

  • B. Kovacic et al.

    c-Src activation plays a role in endothelin-dependent hypertrophy of the cardiac myocyte

    J Biol Chem

    (1998)
  • R. Latini et al.

    Role of brain natriuretic peptide in the diagnosis and management of heart failure: current concepts

    J Card Fail

    (2002)
  • F. Liang et al.

    Autocrine/paracrine determinants of strain-activated brain natriuretic peptide gene expression in cultured cardiac myocytes

    J Biol Chem

    (1998)
  • F. Liang et al.

    Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes

    J Biol Chem

    (2003)
  • F. Liang et al.

    Mechanical strain increases expression of the brain natriuretic peptide gene in rat cardiac myocytes

    J Biol Chem

    (1997)
  • L.M. Luttrell et al.

    Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gbetagamma subunit-mediated activation of mitogen-activated protein kinases

    J Biol Chem

    (1996)
  • K. Maekawa et al.

    Cloning and sequence analysis of cDNA encoding a precursor for porcine brain natriuretic peptide

    Biochem Biophys Res Commun

    (1988)
  • J.D. Molkentin et al.

    A calcineurin-dependent transcriptional pathway for cardiac hypertrophy

    Cell

    (1998)
  • C. Morisco et al.

    Glycogen synthase kinase 3beta regulates GATA4 in cardiac myocytes

    J Biol Chem

    (2001)
  • C. Morisco et al.

    The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes

    J Biol Chem

    (2000)
  • M. Mukoyama et al.

    Human brain natriuretic peptide, a novel cardiac hormone

    Lancet

    (1990)
  • K. Ono et al.

    The p38 signal transduction pathway: activation and function

    Cell Signal

    (2000)
  • S. Pikkarainen et al.

    Endothelin-1-specific activation of B-type natriuretic peptide gene via p38 mitogen-activated protein kinase and nuclear ETS factors

    J Biol Chem

    (2003)
  • S. Pikkarainen et al.

    GATA-4 is a nuclear mediator of mechanical stretch-activated hypertrophic program

    J Biol Chem

    (2003)
  • J.G. Porter et al.

    Cloning of a cDNA encoding porcine brain natriuretic peptide

    J Biol Chem

    (1989)
  • A.M. Richards et al.

    BNP in hormone-guided treatment of heart failure

    Trends Endocrinol Metab

    (2002)
  • J.J. Seilhamer et al.

    Human and canine gene homologs of porcine brain natriuretic peptide

    Biochem Biophys Res Commun

    (1989)
  • G. Shaw et al.

    A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation

    Cell

    (1986)
  • T. Sudoh et al.

    Cloning and sequence analysis of cDNA encoding a precursor for human brain natriuretic peptide

    Biochem Biophys Res Commun

    (1989)
  • E.C. Svensson et al.

    A functionally conserved N-terminal domain of the friend of GATA-2 (FOG-2) protein represses GATA4-dependent transcription

    J Biol Chem

    (2000)
  • Y. Takei

    Does the natriuretic peptide system exist throughout the animal and plant kingdom?

    Comp Biochem Physiol B Biochem Mol Biol

    (2001)
  • N. Tamura et al.

    Two cardiac natriuretic peptide genes (atrial natriuretic peptide and brain natriuretic peptide) are organized in tandem in the mouse and human genomes

    J Mol Cell Cardiol

    (1996)
  • D.J. Thuerauf et al.

    Differential effects of protein kinase C, Ras, and Raf-1 kinase on the induction of the cardiac B-type natriuretic peptide gene through a critical promoter-proximal M-CAT element

    J Biol Chem

    (1997)
  • D.J. Thuerauf et al.

    Regulation of rat brain natriuretic peptide transcription. A potential role for GATA-related transcription factors in myocardial cell gene expression

    J Biol Chem

    (1994)
  • K.K. Tomaru et al.

    Transcriptional activation of the BNP gene by lipopolysaccharide is mediated through GATA elements in neonatal rat cardiac myocytes

    J Mol Cell Cardiol

    (2002)
  • H. Akazawa et al.

    Roles of cardiac transcription factors in cardiac hypertrophy

    Circ Res

    (2003)
  • J.A. Atwater et al.

    Regulated mRNA stability

    Annu Rev Genet

    (1990)
  • H. Bentzen et al.

    Influence of training habits on exercise-induced changes in plasma atrial and brain natriuretic peptide and urinary excretion of aquaporin-2 in healthy man

    Scand J Clin Lab Invest

    (2002)
  • V.A. Cameron et al.

    The sites of gene expression of atrial, brain, and C-type natriuretic peptides in mouse fetal development: temporal changes in embryos and placenta

    Endocrinology

    (1996)
  • L. Cao et al.

    Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts

    Hypertension

    (1995)
  • Y. Daaka et al.

    Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A

    Nature

    (1997)
  • L. Dagnino et al.

    Differential expression of natriuretic peptide genes in cardiac and extracardiac tissues

    Mol Endocrinol

    (1991)
  • U. Elkayam et al.

    Nesiritide: a new drug for the treatment of decompensated heart failure

    J Cardiovasc Pharmacol Ther

    (2002)
  • K.A. Gallo et al.

    Mixed-lineage kinase control of JNK and p38 MAPK pathways

    Nat Rev Mol Cell Biol

    (2002)
  • Cited by (102)

    • Atrial and brain natriuretic peptides: Hormones secreted from the heart

      2019, Peptides
      Citation Excerpt :

      ER stress also induces BNP gene expression in cardiomyocytes [53]. Multiple signaling pathways involving MAPKs including ERK1/2 (p44/p42 MAPK), p38MAPK, JNK, and ERK5, GP130/JAK-STAT, CaMKII, PKCs, PI3K-Akt-GSK3β, Rho-ROCK, and calcineurin-NFATs reportedly contribute to the up-regulation of ANP and/or BNP gene expression induced by mechanical or neurohumoral stimulation [39,54–59] Several cis-acting regulatory elements have been shown to be involved in the basal and inducible expression of ANP and BNP genes.

    • B-type Natriuretic Peptide circulating forms: Analytical and bioactivity issues

      2015, Clinica Chimica Acta
      Citation Excerpt :

      Apart from amino acid sequence differences, each member is distinguished by the length of the amino-terminal (N-terminal) and carboxy-terminal (C-terminal) arms extending from each ring. BNP and ANP are synthesised in both the atria and ventricles of the heart in response to increased transmural pressure or stretch of cardiomyocytes [1,2]. BNP is predominantly synthesised and secreted from ventricular tissue while ANP is mainly secreted from atrial tissue in healthy subjects with an increasing proportion of ANP derived from ventricular tissue in heart failure where secretion rates are high.

    View all citing articles on Scopus
    View full text