Disease relevance of Npr1

• Myocardial fibrosis, total collagen, and the collagen type I/III ratio (p < 0.01) were dramatically increased in adult Npr1-/- mice compared with age-matched wild-type counterparts [1].
• Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure [2].
• We examined the effect of 3 wk of hypobaric hypoxia (0.5 atm) on right and left ventricular pressure and mass in mice with 2 (wild type), 1, or 0 copies of Npr1, the gene that encodes for NPR-A in mice [3].
• A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy [4].
• We conclude that GC-A-mediated increases in endothelial permeability are critically involved in the hypovolemic, hypotensive actions of ANP [5].

Psychiatry related information on Npr1

• Renal C-type natriuretic peptide and natriuretic peptide receptor B mRNA expression are affected by water deprivation in the Spinifex Hopping mouse [6].

High impact information on Npr1

• Here we report that disruption of the GC-A gene results in chronic elevations of blood pressure in mice on a normal salt diet [7].
• Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide [7].
• Furthermore, intravenous ANP acutely enhanced the rate of clearance of radio-iodinated albumin from the circulatory system in control but not in EC GC-A KO mice [5].
• To dissect the endothelium-mediated actions of ANP in vivo, we inactivated the GC-A gene selectively in endothelial cells by homologous loxP/Tie2-Cre-mediated recombination [5].
• Echocardiographic and Doppler flow evaluations together with the Evan's blue dilution technique showed that the total plasma volume of EC GC-A KO mice was increased by 11-13%, even under conditions of normal dietary salt intake [5].

Chemical compound and disease context of Npr1

• Chronic treatment of GC-A(-/-) mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension [8].
• Also, chronic testosterone infusion increased cardiac mass and fibrosis in ovariectomized GC-A mice [9].
• Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A [9].
• In the further studies, either castration (at 10 wk of age) or flutamide, an androgen receptor antagonist, markedly attenuated cardiac hypertrophy and fibrosis in male GC-A KO mice without blood pressure change [9].
• Notably, the enhanced myocardial fibrosis seen in KO mice was virtually absent in infarcted double-KO mice, lacking guanylyl cyclase-A and angiotensin II type 1a receptors, although there was no improvement in survival and no attenuation of cardiac hypertrophy [10].

Biological context of Npr1

• These results demonstrate that below normal Npr1 expression leads to a salt-sensitive increase in blood pressure, whereas above normal Npr1 expression lowers blood pressures and protects against high dietary salt [11].
• Cross-competition experiments with mutated oligonucleotides led to the definition of a consensus sequence (-1372 AaAtRKaNTTCaAcAKTY -1354) for the novel cGMP-RE, which is conserved in the human (75% identity) and mouse (95% identity) Npr1 promoters [12].
• Our results also suggest roles for Npr1 as well as Apoe in regulation of hypertrophic cell growth [13].
• Introduction of the GC-A transgene did not alter blood pressure or heart rate as a function of genotype [4].
• However, introduction of the GC-A transgene reduced cardiac myocyte size in both wild-type and null mice [4].

Anatomical context of Npr1

• Cardiac myocyte size was larger (approximately 20%) in GC-A null than in wild-type animals [4].
• 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 [4].
• C-type natriuretic peptide (CNP), in contrast, caused half-maximal relaxation at concentrations of 335 and 146 nM in aortas from either wild-type or null mice, respectively, suggesting that this peptide acted through a receptor other than GC-A [14].
• 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 [15].
• BACKGROUND: Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts [16].

Associations of Npr1 with chemical compounds

• The natriuretic peptide stimulation of bone growth, which was mimicked by 8-bromo-cGMP, was inhibited by HS-142-1, a non-peptide GC-coupled natriuretic peptide receptor antagonist [17].
• In GC-A -/- hearts, the immediate contractile responses to CNP and 8-pCPT-cGMP were significantly enhanced [18].
• Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling [19].
• Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart [16].
• The results demonstrate that all 4 pathways were activated in GC-A(-/-) mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment [8].
• Treatment of mice with angiotensin II (300 ng/kg/min during 7 days) resulted in enhanced pulmonary mRNA expression of spliced GC-A, which was concomitant to diminished GC-A/cGMP responses to ANP [20].

Physical interactions of Npr1

• We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice [16].
• NF-kappaB binding activity was 4-fold greater in the nuclear extract of Npr1-/- mutant mice hearts as compared with wild-type (Npr1+/+) mice hearts [21].
• In peripheral organs BNP binds to the natriuretic peptide receptor type A causing increased intracellular cGMP production [22].
• The constructs having a mutant Ets-1 binding site or lacking this site failed to respond to Ets-1 activation of Npr1 gene transcription [23].

Regulatory relationships of Npr1

• In contrast, CNP induced concentration-dependent vasorelaxations of GC-A -/- and SMC GC-A KO RRA [24].
• The NPR-A is selectively expressed by LLC-PK1 epithelial cells and the NPR-B by NIH-3T3 fibroblast cells [25].
• Direct inhibition of CaMKII activation by KN93 (0.5 or 2 microM) or inhibition of Ca(2+)/calmodulin-dependent activation of CaMKII by W-7 (25 microM) suppressed pVT in GC-A-/- hearts (P < 0.05) while prolonging APD [26].
• Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-kappaB activation and alleviates myocardial ischemia/reperfusion injury [27].
• RESULTS: AlbuBNP had approxiamtely the same maximal bioactivity as BNP to activate cGMP in the in vitro NPRA/cGMP assay [28].

Other interactions of Npr1

• The biological actions of natriuretic peptides are thought to be mediated through the activation of two guanylyl cyclase (GC)-coupled receptor subtypes (GC-A and GC-B) [17].
• Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide [15].
• METHODS AND RESULTS: We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866 [16].
• 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 [15].
• Increased effects of C-type natriuretic peptide on cardiac ventricular contractility and relaxation in guanylyl cyclase A-deficient mice [18].

Analytical, diagnostic and therapeutic context of Npr1

• Macrophages were shown to express all three natriuretic peptide receptors (NPR-A, NPR-B, NPR-C) using RT-PCR technique [29].
• Neither castration nor testosterone administration induced any change in the cardiac phenotypes of double-KO mice for GC-A and AT1A [9].
• The messages for GC-A and GC-B were demonstrated by means of Northern blot analysis, and the presence of CNP was shown by Southern blotting coupled with reverse transcription-polymerase chain reaction (RT-PCR) [30].
• In conscious mice with an indwelling catheter, the infusion of a physiological saline solution containing 4% BSA resulted in a marked natriuresis/diuresis in wild-type mice but no response in GC-A null animals [31].
• Northern blot analysis showed that mRNA specific for guanylyl cyclase type A (Npra) was expressed at approximately twofold higher levels in WKY than in SHR testis [32].

References