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

• The effect of water deprivation on the expression of atrial natriuretic peptide and its receptors in the spinifex hopping mouse, Notomys alexis [4].
• The data demonstrate an influence of ANP on important defense mechanisms of macrophages and thus extend the knowledge regarding the pharmacological profile of this natriuretic peptide [5].

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

• Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan [9].
• Because renal blood flow, as measured by radioactive microspheres, decreased significantly in all four groups, probably due to nonspecific renal vasoconstrictor effects of the ascites, a separate group of infarcted animals was treated with purified ANF antibody (devoid of nonspecific effects) or mouse IgG as a control injection [10].
• We show that ANF transcription is activated directly by the AII type 1 receptor and precedes the development of myocyte hypertrophy [11].
• Our observations suggest that endogenous ANP inhibits cardiac myocyte hypertrophy under basal and PE-stimulated conditions, probably through a cGMP-dependent process [12].
• This concept has been strengthened by the purification and biochemical characterization of a 180 kDa protein, which appears to contain both ANF receptor and guanylate cyclase activities, from rat adrenocortical carcinoma cells [13].

Biological context of Nppa

• Many aspects of the regulatory pathways that control Nppa gene expression during cardiac development or disease have been revealed [14].
• Mid-wall shortening was mildly depressed in the Nppa(-/-) vs. Nppa(+/+) genotype following ACF with fed 0.55% NaCl [1].
• These results show that, in chicken, the Nppa gene has been lost from the natriuretic peptide precursor gene cluster, whereas the CNP-3 gene has been retained [15].
• Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood pressure [3].
• 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 [16].

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

• 5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements [18].
• Enzyme assays and NPRA-specific Western blots performed on tissues from wild-type mice demonstrate that ANP-activated cGMP synthesis provides a good index of NPRA protein expression, which ranges from maximal in adrenal gland, lung, kidney, and testis to minimal in heart and colon [25].
• The function of Tbx3 in regulating Nppa and Cx40 promoter activity was studied in vitro [26].
• In contrast, activation of GCA by atrial natriuretic peptide (10(-6) mol/L) inhibited phenylephrine (10(-6) mol/L)-stimulated nuclear translocation of NFATc3 [27].
• IL-18 has also been shown to induce atrial natriuretic factor (ANF) gene expression in adult cardiomyocytes [28].

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].

References