Molecular regulation of the brain natriuretic peptide gene
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.
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2019, PeptidesCitation 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.
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2015, Clinica Chimica ActaCitation 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.