Disease relevance of Nppb

• No signs of systemic hypertension and ventricular hypertrophy are noted in Nppb(-/-) mice [1].
• Transgenic mice with elevated plasma BNP concentrations exhibited deformed bony skeletons characterized by kyphosis, elongated limbs and paws, and crooked tails [2].
• No signs of cardiac hypertrophy and systemic hypertension were noted in BNP-/- mice [3].
• Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders [3].
• Brain natriuretic peptide (BNP) is a cardiac hormone produced primarily by ventricular myocytes, and its plasma concentrations are markedly elevated in patients with congestive heart failure and acute myocardial infarction [1].

High impact information on Nppb

• These animals showed 10- to 100-fold increase in plasma BNP concentration accompanied by elevated plasma cyclic GMP concentration, and had significantly lower blood pressure than their nontransgenic littermates [4].
• The mouse BNP gene was organized into three exons and two introns [4].
• In transgenic (Tg) mice that overexpress BNP in response to hindlimb ischemia, neovascularization with appropriate mural cell coating was accelerated without edema or bleeding, and impaired angiogenesis by the suppression of nitric oxide production was effectively rescued [5].
• In response to ventricular pressure overload, focal fibrotic lesions are increased in size and number in Nppb(-/-) mice, whereas no focal fibrotic changes are found in wild-type littermates (Nppb(+/+) mice) [1].
• The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type [6].

Chemical compound and disease context of Nppb

• These haemodynamic effects probably contribute to the side-effects of BNP in patients with acute CHF with a 27% incidence of hypotension and possibly to 22% worsening of renal function, defined as an increase in serum creatinine of 0.5 mg/dL, associated with a worse prognosis [7].
• We therefore compared angiotensin (Ang) II-induced cardiac hypertrophy and fibrosis in BNP-transgenic (Tg) mice, in which circulating BNP levels were elevated by increased secretion from the liver, and their non-Tg littermates [8].
• Left ventricular hypertrophy was observed on echocardiography (1.25+/-0.05 mm vs. 0.86+/-0.02 mm in cTnI-wt, P<0.01), associated with a significant 4-fold increase in RNA markers of hypertrophy, ANF and BNP [9].
• Myocyte cross-sectional area, a measure of hypertrophy, was decreased by 30% in the NS-398 versus vehicle group, but there was no effect on BNP mRNA [10].

Biological context of Nppb

• Studies using an in vitro organ culture of embryonic mouse tibias revealed that BNP increases the height of cartilaginous primordium directly, thereby stimulating the total longitudinal bone growth [2].
• The ANP and BNP gene expressions are markedly augmented in ventricles of patients with a wide variety of cardiovascular diseases [11].
• Such an autoregulatory pathway may represent an important physiological homeostatic mechanism and link the paracrine activity of NO and CNP with the endocrine functions of ANP and BNP in the regulation of vascular tone and blood pressure [12].
• It has been demonstrated that the ANP and BNP genes are tightly linked on mouse chromosome 4 and on the distal short arm of human chromosome 1 [11].
• By polymerase chain reaction, we isolated an approximately 11-kb human genomic DNA fragment containing the third exon of the BNP gene and the first and second exons of the ANP gene [11].

Anatomical context of Nppb

• However, testis and adrenal gland retain statistically significant, high-affinity responses to BNP [13].
• Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which act as cardiac hormones, are produced mainly by the atrium and ventricle, respectively, and are involved in body fluid homeostasis and blood pressure control [11].
• Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP-/- mice [3].
• ANP and BNP (300 ng) reduced pulmonary artery pressure during acute hypoxia-induced pulmonary vasoconstriction in +/+ mice, but this effect was attenuated in +/- and absent in -/- mice [14].
• In mouse placenta, strong CNP expression was seen in the decidua basalis around the large maternal blood vessels, and BNP message was detected at the peripheral margin of the decidual layer [15].

Associations of Nppb with chemical compounds

• The proteolytic processing site (RXXR-S) generating bioactive BNPs was highly conserved among all BNP precursors and was identical to the consensus site of furin, a calcium-dependent serine endoprotease [16].
• This effect was receptor specific, because pretreatment with sodium nitroprusside (an activator of nitric oxide-sensitive guanylyl cyclase), or with ANP or BNP, did not cause desensitisation of CNP-stimulated cGMP accumulation [17].
• Mass spectroscopic analysis confirmed that ANP is rapidly cleaved at the first cysteine of the disulfide ring, whereas BNP is particularly stable to such cleavage [18].
• ANF and BNP enhanced the stimulatory effect of LH on testosterone production [19].
• ANF, BNP, and CNP stimulated the production of intermediate precursors of testosterone biosynthesis, which included progesterone, 17 alpha-hydroxy progesterone, androstenedione, pregnenolone, 17 alpha-hydroxy pregnenolone, and dehydroepiandrosterone sulfate [19].

Physical interactions of Nppb

• In peripheral organs BNP binds to the natriuretic peptide receptor type A causing increased intracellular cGMP production [20].

Regulatory relationships of Nppb

• In the heart, the BNP gene expression is regulated differently from the ANP gene expression both at transcriptional and post-transcriptional levels [21].
• In the failing adult ventricle, ANF and BNP were up-regulated to the same extent in wild-type and Nkx2-5+/- myocardium [22].
• RESULTS: AlbuBNP had approxiamtely the same maximal bioactivity as BNP to activate cGMP in the in vitro NPRA/cGMP assay [23].

Other interactions of Nppb

• Natriuretic peptides organize a family of three structurally related peptides: atrial natriuretic peptide, brain natriuretic peptide (BNP), and C-type natriuretic peptide [2].
• The family of rGCs is rapidly expanding, and it is plausible that there might be additional, as yet undiscovered, rGCs whose function is to provide alternative signalling pathways for one or both of these peptides, particularly given the low affinity of NPRA for BNP [13].
• In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP-/- mice examined, accompanied by further increase of mRNA expression of TGF-beta3 and Col alpha1(I) [3].
• CONCLUSIONS: Increased BNP-mRNA levels in hypertensive ANG-overexpressing mice and decreased BNP in hypotensive AT1-deficient animals suggest that this mRNA expression is blood pressure-dependent [24].
• However, the observed alterations of fibrosis and the unchanged BNP in hypotensive ANG knockouts and impaired BNP-mRNA expression in normotensive AT2-deficient mice demonstrate a direct interaction of the RAS and NPS that is fibrosis- rather than blood pressure-dependent [24].

Analytical, diagnostic and therapeutic context of Nppb

• 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 [15].
• A new radioimmunoassay (RIA) was developed in order to measure mouse BNP peptide levels in the plasma, atrium and ventricle of the mouse [25].
• 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 [25].
• The hearts were serially sectioned and processed for immunohistochemistry, with antisera against ANP and brain natriuretic peptide (BNP) [26].
• In the outgrowths of embryoid bodies in vitro, gene expression of ANP and BNP was detected by RT-PCR and granules positive for the peptides were identified in a few cardiomyocytes by light and electron microscopic immunocytochemistry [27].

References