Disease relevance of Nppb

• 1. The natriuretic peptide precursor A (Nppa) and B (Nppb) genes are candidate genes for hypertension and cardiac hypertrophy in the spontaneously hypertensive rat (SHR) [1].
• Brain natriuretic peptide (BNP) gene expression is a well documented marker of hypertrophy in the cardiac myocyte [2].
• We have examined the temporal relationship between the expression of mRNA transcripts for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and their receptors in the heart during the development of cardiac hypertrophy in the aortovenocaval fistula rat [3].
• We have also reported that, compared with atrial natriuretic peptide (ANP), the plasma concentration of BNP is increased to a greater degree in patients with congestive heart failure and more rapidly in patients with acute myocardial infarction (AMI) [4].
• Therefore, the effects of chronic excess of BNP on anti-glomerular basement membrane nephritis induced in BNP-transgenic mice (BNP-Tg) were investigated and the mechanisms how natriuretic peptides act on mesangial cells in vitro were explored [5].

High impact information on Nppb

• Application of mechanical strain to neonatal rat ventricular myocytes in culture evokes changes in gene expression reminiscent of those that occur with hypertrophy in vivo, such as stimulation of brain natriuretic peptide (BNP) gene expression [6].
• This activation may play an important role in signaling the increased BNP gene expression that accompanies hemodynamic overload and cardiac hypertrophy in vivo [6].
• Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1 [7].
• During cardiocyte hypertrophy evoked by endothelin-1, Phenylephrine, or PMA, the steady state level of BNP mRNA increased as rapidly as the "immediate-early" induction of the c-fos gene expression, and reached a maximal level within 1 h [8].
• In hamsters, BNP and ANP occur mainly in the ventricle and the atrium, respectively [9].

Chemical compound and disease context of Nppb

• Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes [2].
• The combination of these actions resulted in repressing the reactivation of ANP and BNP, and ultimately preventing the progress of cardiac hypertrophy [10].
• Posttranscriptional control of BNP gene expression in angiotensin II-induced hypertension [11].
• In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage) [12].
• Results suggest that both rat ANP-(1-28) and rat BNP-45 are markedly increased in plasma in DOCA-salt-induced malignant hypertension of SHR and that the major source of circulating BNP is the hypertrophied ventricles in this model [13].

Biological context of Nppb

• No association was found between the Nppb gene and blood pressure [1].
• Since brain natriuretic peptide (BNP) is activated early in cardiac growth and development, we evaluated whether it could serve as a target gene for GATA-binding protein-mediated induction [14].
• Upon isolating and sequencing 2.5 kilobases of the rat BNP 5'-flanking sequence (FS), a variety of putative transcriptional enhancer sites were identified, including several GATA consensus sequences (WGATAR), one of which apparently serves as the major promoter site [14].
• Truncation analyses showed that inducibility mapped primarily to the proximal -116 base pair of the rat BNP 5'-FS, where there are two consensus GATA sites in addition to the GATA sequence at the TATA box [14].
• Transcriptional activation of the BNP gene by lipopolysaccharide is mediated through GATA elements in neonatal rat cardiac myocytes [15].

Anatomical context of Nppb

• In this study, reporter constructs transfected into neonatal rat ventricular myocytes showed that in the context of 2.5 kilobase pairs of native BNP 5'-flanking sequences, a 2-base pair mutation in a promoter-proximal M-CAT site (CATTCT) disrupted basal and PE-inducible transcription by more than 98% [16].
• Thus BNP, which increases cyclic GMP independently of NO, is an important approach to prevent growth in the diabetic myocardium, where endothelium-dependent mechanisms are compromised [17].
• To study the molecular mechanisms for load-induced activation of BNP gene expression, increased wall stress was imposed on isolated isovolumetrically beating adult rat hearts by distension of a fluid filled balloon within the left ventricle [18].
• Progressive cardiac hypertrophy was accompanied by increased ANP mRNA prevalence throughout the heart and increased BNP mRNA in the left atrium [3].
• METHODS AND RESULTS: To investigate ventricular gene expression of BNP in AMI, we analyzed plasma and ventricular BNP concentrations along with ventricular BNP mRNA in rats with AMI produced by coronary artery ligation [4].

Associations of Nppb with chemical compounds

• Although inducible elements in the ANP gene have been identified, responsible elements in the BNP gene are unknown [16].
• However, the blunting of hypertrophic markers and accompanying increases in cyclic GMP stimulated by BNP were preserved in diabetes [17].
• Isolated M-CAT elements conferred PE, protein kinase C, and Ras inducibility to a minimal BNP promoter, however, they did not confer Raf-1 inducibility [16].
• LPS-mediated BNP expression was completely inhibited by the pretreatment of SB203580, a specific inhibitor for p38 MAPK as well as by genistein, a broad range tyrosine kinase inhibitor [15].
• The MLR-induced increases in BNP secretion were completely abolished by SB203580 pre-treatment [19].

Regulatory relationships of Nppb

• The mixed endothelin-1 ET(A)/ET(B) receptor antagonist bosentan but not the angiotensin II type 1 receptor antagonist losartan completely inhibited the pressure overload-induced increase in left ventricular BNP GATA4 binding activity [20].

Other interactions of Nppb

• Cotransfection of the expression vectors for constitutive active forms of Rac1, MKK3 and p38 MAPK significantly increased BNP promoter activity [15].
• There was no correlation between the Nppa or Nppb genes or other markers in this region and either heart weight or left ventricular weight in F2 rats [1].
• Several of the genes upregulated in the hypertrophied heart, including B-type natriuretic peptide (BNP) gene, are controlled by the cardiac-restricted zinc finger transcription factor GATA4 [20].
• ANF, BNP, as well as alpha- and beta-myosin heavy chain (MHC) mRNA were estimated by Northern blot analysis [21].
• Pressure overload within 15 to 60 minutes produced an increase in left ventricular BNP GATA4 but not GATA5 and GATA6 binding activity, and at 30 minutes a 2.2-fold increase (P:<0.001) in GATA4 binding was noted [20].

Analytical, diagnostic and therapeutic context of Nppb

• Northern blot analysis showed that LPS induces the expression of the BNP gene [15].
• This study tested pro-inflammatory cytokines or conditioned medium (CM) derived from mixed- lymphocyte reaction (MLR) cultures in their ability to modulate ANF or BNP mRNA expression, secretion, as well as BNP promoter activity in cultured neonatal rat cardiocytes [19].
• An increase in circulating brain natriuretic peptide (BNP) but not atrial natriuretic factor (ANF) is observed coincident with cardiac allograft rejection that is reversed upon treatment with anti-lymphocyte therapy suggesting that pro-inflammatory cytokines may uniquely modulate BNP gene expression and secretion [19].
• By using a radioimmunoassay (RIA) system newly established for rat BNP, a high concentration of ir-BNP was found to exist in rat cardiac atrium [22].
• Two ir-BNPs of different molecular weights (11K and 5K) were isolated from rat cardiac atria by anti-rat BNP IgG immunoaffinity chromatography and reverse phase high performance liquid chromatography (HPLC) [22].

References