• bone;
  • cardiac hypertrophy;
  • guanylyl cyclase;
  • hypertension;
  • natriuretic peptide


  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References

The mammalian natriuretic peptide system, consisting of at least three ligands and three receptors, plays critical roles in health and disease. Examination of genetically engineered animal models has suggested the significance of the natriuretic peptide system in cardiovascular, renal and skeletal homeostasis. The present review focuses on the in vivo roles of the natriuretic peptide system as demonstrated in transgenic and knockout animal models.


atrial natriuretic peptide


brain natriuretic peptide


C-type natriuretic peptide


guanylyl cyclase


myocyte-enriched calcineurin-interacting protein


protease-activated receptor


cGMP-dependent protein kinase


regulator of G-protein signaling

Natriuretic peptides

  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References

The existence of an atrial factor with diuretic and natriuretic activities has been postulated since 1981 [1]. In 1983–1984, the isolation and purification of such a factor and determination of its amino acid sequence were accomplished in rats and humans [2–7]. The factor is a peptide distributed mainly in the right and left cardiac atria within granules of myocytes and thus called atrial natriuretic factor or atrial natriuretic peptide (ANP). The discovery of ANP revealed that the heart is not only a mechanical pump driving the circulation of blood but also an endocrine organ regulating the cardiovascular–renal system. For instance, in situations of excessive fluid volume, cardiac ANP secretion is stimulated, which causes vasodilatation, increased renal glomerular filtration and salt/water excretion and inhibition of aldosterone release from the adrenal gland, which collectively result in a reduction of body fluid volume.

Later, in 1988, a homologous peptide with similar biological activities was isolated from porcine brain and hence was named brain natriuretic peptide (BNP) [8]. However, it was soon found that brain BNP levels were much lower in other species. It has since been shown that BNP is mainly produced and secreted by the heart ventricles [9]. Synthesis and secretion of BNP are regulated differently from ANP [10], and the plasma concentration of BNP has been found to reflect the severity of heart failure more closely than ANP [11].

In 1990, yet another type of natriuretic peptide was isolated from porcine brain and named C-type natriuretic peptide (CNP) [12]. CNP was initially thought to function only in the brain but was later shown to be produced in peripheral tissues such as the vascular endothelium [13] and in smooth muscle cells and macrophages [14]. Because CNP plasma levels are considerably lower than those of ANP or BNP, CNP is thought to mainly act locally as a paracrine factor rather than as a circulating hormone.

Natriuretic peptide receptors

  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References

To date, three receptors for natriuretic peptides have been identified. In 1988, one type of ANP receptor was isolated from cultured vascular smooth muscle cells. Using its partial amino acid sequence, the full-length cDNA was cloned and the entire amino acid sequence was deduced [15]. The receptor molecule consists of 496 amino acid residues and contains a large extracellular domain, a putative single transmembrane helix and a 37 amino acid residue cytoplasmic domain. It is generally accepted that the role of this receptor is to bind and remove natriuretic peptides and their fragments from the circulation. Hence, this receptor is termed natriuretic peptide clearance receptor (C receptor). On the other hand, a signaling role of the C receptor has also been suggested [16].

One of the earliest events following the binding of ANP to its receptor is increase in the cytosolic cyclic guanosine monophosphate (cGMP) levels. This finding suggested that cGMP might act as the second messenger mediating the physiological activities of ANP and that the ANP receptor is coupled to guanylyl cyclase (GC), the enzyme that catalyzes the generation of cGMP. In 1989, a segment of the sea urchin GC cDNA was used as a probe to screen various cDNA libraries, which enabled cloning of the first mammalian GC (thus called GC-A) from rats and humans [17]. Expression of the cloned enzyme confirmed that GC-A is an ANP receptor. Soon after the discovery of GC-A, cloning of a second mammalian GC (GC-B) was reported [18,19]. GC-B also bound and was activated by natriuretic peptides, demonstrating the diversity within the natriuretic peptide receptor family. Since these receptor proteins were first identified as GC family members, we refer to them as GC-A or GC-B throughout this paper.

Ligand selectivity

  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References

Subsequent studies revealed that GC-A preferentially binds and responds to ANP, while GC-B preferentially responds to CNP [20]. The relative effectiveness of the three natriuretic peptides in stimulating cGMP production via GC-A and GC-B has been reported [21]. The rank order of potency for cGMP production via the GC-A receptor was ANP ≥ BNP >> CNP. On the other hand, cGMP response via GC-B was CNP > ANP or BNP. Thus, the biological functions of natriuretic peptides are mediated by two receptors: GC-A (also known as the A-type natriuretic peptide receptor, NPRA), which is selective for the cardiac peptides ANP and BNP, and GC-B (also called the B-type natriuretic peptide receptor, NPRB), which is selective for CNP.

The binding affinities of ANP, BNP and CNP to the human or rat C receptor have been reported [21]. Irrespective of the species examined, the rank order of affinity for the C receptor was ANP > CNP > BNP. This finding suggests that BNP is the least susceptible to C-receptor-mediated clearance and is more stable in the plasma.

Lessons from genetically engineered animals

  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References

A variety of genetically engineered mice have been generated to study the physiological function of each component of the natriuretic peptide–receptor system (summarized in Table 1).

Table 1.   Phenotypes of the genetically engineered animals for the natriuretic peptide system.
Mutated geneTargeting constructTargeted tissueBlood pressure phenotypeCardiac phenotypeOther phenotypes
ANP overexpression [22]Mouse transthyretin promoter/mouse ANP fusion geneLiver∼ 25 mmHg lower than the control27% reduction in heart weightPlasma ANP elevated 8-fold or more; 21% reduction in peripheral resistance
ANP knockout [24]11 bp in exon-2 replaced with the neomycin resistance geneSystemic disruptionIncrease, 8–23 mmHg (homozygotes); normal on standard diet; 27 mmHg increase on high-salt diet (heterozygotes)Heart to body weight ratio 1.4-fold higher than the wild-typeHeterozygotes have normal level of circulating ANP
BNP overexpression [23]Human serum amyloid P component/mouse BNP fusion geneLiver∼ 20 mmHg lower than non-transgenic littermates∼ 30% less heart weight than non-transgenic littermates10- to 100- fold increase in plasma BNP concentration; skeletal overgrowth
BNP knockout [31]Exons 1 and 2 replaced with the neomycin resistance geneSystemic disruptionNo signs of systemic hypertensionNo signs of ventricular hypertrophy; pressure-overload-induced focal ventricular fibrosis 
CNP overexpression in the cartilage [63]Col2a1 promoter region/mouse CNP fusion geneGrowth plate cartilageNot reportedNot reportedLongitudinal overgrowth of bones (limbs, vertebrae, skull)
CNP overexpression in the liver [64]Human serum amyloid P component/mouse CNP fusion geneLiverSystolic blood pressure unaffectedHeart weight unaffectedElongation of cartilage bones; plasma CNP level is 84% higher than control
CNP overexpression in the heart [65]CNP gene fused downstream of the murine α-myosin heavy chain promoterHeartNo changeNo change at baselineVentricular hypertrophy after myocardial infarction is prevented
CNP knockout (Kyoto) [59]Exons 1 and 2 encoding CNP replaced with the neomycin resistance geneSystemic disruptionNot reportedNot reportedSevere dwarfism: impaired endochondral ossification; impaired nociceptive neurons [62]
CNP knockout (Berlin) [66]Exon 1 replaced with a lacZ expression cassetteSystemic disruptionNot reportedNot reportedLack of bifurcation of sensory axons in the embryonic dorsal root entry zone
GC-A knock-in overexpression [27]Entire GC-A gene duplicated with the neomycin resistance gene in betweenSystemic overexpressionAverage 5.2 mmHg below normal in F1 mice carrying three copies of the GC-A geneNo effect on heart weights 
GC-A overexpression in the heart [39]GC-A gene fused downstream of murine α-myosin heavy chain promoterHeartNormal blood pressureHeart weight to body weight ratio was significantly less by ∼ 15% 
GC-A knockout (Dallas) [25]Neomycin resistance gene inserted in exon 4, which encodes the transmembrane domainSystemic disruptionSystolic blood pressure is 20–25 mmHg higher than wild-typeGlobal cardiac hypertrophy (40–60% increase in heart weight); cardiac contractility similar to that in wild-type miceRapid increases in urine output, urinary sodium and cGMP excretion after plasma volume expansion are abolished; increased susceptibility to hypoxia-induced pulmonary hypertension
GC-A knockout (North Carolina) [26]Exon 1, intron 1 and a portion of exon 2 were replaced with the neomycin resistance geneSystemic disruption16 mmHg higher than the controlHeart to body weight ratio averaging185% (male) and 133% (female) of wild-typeSudden death, with morphological evidence indicative of congestive heart failure or of aortic dissection; resistant to LPS-induced fall in blood pressure
GC-A conditional knockoutTargeting vector contains exons 1–13 and an additional 3.8 kb of the 5′ sequence of the GC-A gene, a loxP-flanked neomycin resistance cassette (at −2.6 kb of exon 1) and a third loxP site in the middle of intron 1Cardiomyocytes (by crossing with cardiac α-myosin heavy chain promoter Cre mice) [43]7–10 mmHg below normal (due to increased secretion of cardiac natriuretic peptides)20% increase in heart to body weight ratio compared with floxed GC-A mice; ventricular collagen fractions unaffected; preserved cardiac contractility; decreased cardiac relaxation; markedly impaired cardiac function after pressure overload∼ 2-fold increase in plasma ANP concentration
  Smooth muscle cells (by crossing with SM22-Cre mice) [33]Normal; acute effect of exogenous ANP on blood pressure abolishedHeart weight and heart to body weight ratio are not different from wild-typeExaggerated blood pressure response to acute plasma volume expansion; higher vasodilatation sensitivity to nitric oxide and enhanced expression of soluble guanylyl cyclase
  Vascular endothelial cells (by crossing with Tie2 promoter/enhancer Cre mice) [32]Elevated systolic blood pressure by 12–15 mmHg∼ 20% increase in heart weightPlasma volume is increased by 11–13%; increased vascular permeability in response to ANP is abolished
GC-B dominant negative overexpression in rat [67]Dominant-negative mutant for GC-B was fused with the CMV promoterWhole bodyNo significant differences in systolic, diastolic and mean arterial pressureProgressive cardiac hypertrophy, which was further enhanced in chronic volume overloadReduced bone growth; modestly increased heart rate
GC-B dominant negative overexpression in mouse [60]Dominant-negative mutant for GC-B, fused with promoter/enhancer regions of murine pro-α 1(II) collagen gene (Col2a1)CartilageNot reportedNot reportedSignificantly shorter nasoanal length
GC-B knockout [60]Exons 3–7, encoding the C-terminal half of the extracellular ligand-binding domain and the transmembrane segment, were replaced by the neomycin resistance geneSystemic disruptionNo significant differences in blood pressureNot reportedImpaired endochondral ossification, longitudinal vertebra or limb-bone growth; female infertility; impaired female reproductive tract development
C receptor knockout [28]Most of exon 1 was replaced by the neomycin resistance geneSystemic disruption8 mmHg below normalNot reportedLonger half-life of circulating ANP; reduced ability to concentrate urine; skeletal deformities with increased bone turnover

Role of ANP- and BNP-mediated GC-A signaling in blood pressure regulation

Transgenic animals, which constitutively express a fusion gene consisting of the transthyretin promoter and the ANP gene, have plasma ANP levels that are higher than non-transgenic littermates by 5–10 fold [22]. The mean arterial pressure in the transgenic animals was reduced by 24 mmHg, which was accompanied by a 27% reduction in total heart weight. This chronic reduction in blood pressure was due to a 21% reduction in total peripheral resistance, whereas cardiac output, stroke volume and heart rate were not significantly altered. In 1994, transgenic mice carrying the human serum amyloid P component/mouse BNP fusion gene were generated so that the hormone expression is targeted to the liver [23]. The animals exhibited 10- to 100-fold increase in plasma BNP concentration and significantly lower blood pressure than their non-transgenic littermates.

In 1995, ANP-deficient mice were generated, and their blood pressure phenotype was reported [24]. The mutant mice (homozygous null for the ANP gene) had no circulating or atrial ANP, and their blood pressures were significantly higher (8–23 mmHg) than the control mice when they were fed standard diets. When fed a standard-salt (0.5% NaCl) diet, the heterozygotes had normal circulating ANP levels and blood pressures. However, on high-salt (8% NaCl) diets, they were hypertensive, with 27 mmHg increases in systolic blood pressure levels [24].

In the same year, disruption of the GC-A gene was reported to result in chronically elevated blood pressure (about 25 mmHg in systolic pressure) in mice on a standard-salt diet [25]. Unlike mice heterozygous for the ANP gene, blood pressures of GC-A heterozygotes remained elevated and unchanged despite increasing dietary salt intake. In 1997, another group reported that the mice lacking functional Npr1 gene, which encodes GC-A (denominated NPRA by the authors), displayed elevated blood pressure and cardiac hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease [26]. In a subsequent paper, the blood pressures of one-copy F1 animals were reported to be significantly higher on high-salt diet than on low-salt diet [27]. The reason for the discrepancy between the salt phenotypes of these two GC-A knockout mouse strains is still unknown. It is possible that differences result from different targeting strategies or the genetic background of the mouse strains used.

In 1999, the generation of mice in which the C receptor was inactivated by homologous recombination was reported [28]. C-receptor-deficient mice have less ability to concentrate urine, exhibit mild diuresis and tend to have depleted blood volume. C receptor homozygous mutants have significantly lower blood pressures (by 8 mmHg) than their wild-type counterparts. The half-life of ANP in C-receptor-deficient mice is two-thirds longer than that in wild-type mice, demonstrating that C receptor plays a significant role in its clearance. Moreover, C receptor modulates the availability of the natriuretic peptides to their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs. In fact, C receptor expression is tightly regulated by other signaling molecules, such as angiotensin II [29] and catecholamines [30]. Interestingly, the baseline levels of ANP and BNP were not higher in the C-receptor-deficient mice than in the wild-type mice, implying that either the cardiac secretion or C-receptor-independent clearance mechanism was altered in those mice.

In 2000, the targeted disruption of the BNP gene in mice was reported. Multifocal fibrotic lesions were found in the ventricles of BNP-deficient mice, suggesting the protective role of BNP in pathological cardiac fibrosis [31]. Interestingly, there were no signs of systemic hypertension or ventricular hypertrophy, suggesting that in the presence of ANP basal levels of BNP are dispensable for these cardiovascular phenotypes.

To examine the tissue(s) responsible for the hypertensive phenotype of systemic GC-A-null mice, a targeting strategy was designed so that Cre recombinase mediates the deletion of exon 1 of the GC-A gene. Thus, in floxed GC-A mice, GC-A can be deleted in a tissue-specific manner. Endothelium-specific deletion of GC-A was achieved by crossing the floxed GC-A mice with transgenic mice expressing Cre recombinase under the control of the Tie2 promoter/enhancer. Endothelium-specific GC-A-deficient mice display significantly increased systolic blood pressure (by approximately 12–15 mmHg) and diastolic blood pressure (by approximately 5–10 mmHg) than their control littermates [32]. Interestingly, although the direct vasodilatation effects of exogenously administered ANP were abolished, smooth-muscle-cell-restricted deletion of GC-A did not affect the resting blood pressure [33], indicating that endothelial cell GC-A, and not vascular smooth muscle cell GC-A, is indispensable for chronic regulation of blood pressure.

Overall, these results show the significance of the endogenous natriuretic peptide system in the maintenance of normal blood pressure.

Regulation of blood volume

Infusion of ANP results in substantial natriuresis and diuresis in wild-type mice but fails to cause significant changes in sodium excretion or urine output in GC-A-deficient mice, indicating that GC-A is essential for ANP-induced acute regulation of diuresis and natriuresis [34]. After experimental expansion of the plasma volume, urine output as well as urinary sodium and cGMP excretion increase rapidly and markedly in the wild-type but not in systemic GC-A-deficient animals. Nevertheless, plasma ANP levels are comparable or even higher in CG-C-deficient animals [34]. On the contrary, the knock-in overexpression of GC-A (four-copy) in mice results in augmented responses to volume expansion in urinary flow and sodium excretion along with rises in both glomerular filtration rate and renal plasma flow, compared with wild-type (two-copy) mice after volume expansion [35]. These results establish that GC-A activation is the predominant mechanism mediating the natriuretic, diuretic and renal hemodynamic responses to acute blood volume expansion.

The plasma volumes of animals completely lacking GC-A are expanded by 30%, suggesting the role of GC-A in chronic regulation of the blood volume. Interestingly, mice lacking GC-A specifically in the vascular endothelium are volume expanded by 11–13% [32], suggesting that GC-A in the endothelium at least partly accounts for chronic blood volume regulatory effects. Since previous experiments indicated that ANP increased capillary permeability of the endothelium to macromolecules like albumin [36], these data suggest that the ANP/GC-A pathway regulates chronic transvascular fluid balance by increasing microvascular permeability [37].

Cardiac remodeling and the local natriuretic peptide system

Cardiac synthesis and secretion of ANP and BNP are increased according to the severity of cardiac remodeling in humans as well as in animal models [38]. Since the two cardiac natriuretic peptides share a common receptor (i.e. GC-A), the cardiac phenotype of mice lacking GC-A revealed complete effects of the cardiac natriuretic peptide signaling. Notably, targeted deletion of the GC-A gene resulted in marked cardiac hypertrophy and fibrosis, which were disproportionately severe [39,40] given the modest rise in blood pressure [25]. Since the chronic treatment of GC-A-deficient mice with anti-hypertensive drugs, which reduce blood pressure to levels similar to those seen in wild-type mice, has no significant effect on cardiac hypertrophy [41], these results imply that the natriuretic peptides/GC-A system has direct anti-hypertrophic effects in the heart, which are independent of its roles in blood pressure and body fluid control.

More direct evidence of local anti-hypertrophic GC-A signaling was obtained from animals in which the GC-A gene was conditionally targeted. The GC-A gene was selectively overexpressed in the cardiomyocytes of wild-type or GC-A-null animals, and the effects were examined [39]. Whereas introduction of the GC-A transgene did not alter blood pressure or heart rate as a function of genotype, it did reduce cardiomyocyte size in both wild-type and null backgrounds. The reduction in myocyte size was accompanied by a decrease in cardiac ANP mRNA expression, which suggests the existence of a local regulatory mechanism that governs cardiomyocyte size and gene expression via a GC-A-mediated pathway [42]. Conversely, the GC-A gene was inactivated selectively in cardiomyocytes by homologous loxP/Cre-mediated recombination, which circumvents the systemic hypertensive phenotype associated with germline disruption of the GC-A gene [43]. Mice with cardiomyocyte-restricted GC-A deletion exhibited mild cardiac hypertrophy with markedly increased transcription of cardiac hypertrophy markers, including ANP. These observations are consistent with the idea that a local function of the ANP/GC-A system is to moderate the molecular program of cardiac hypertrophy [44].

Since the diuretic, natriuretic and vasorelaxant activities of ANP and BNP lead to reduction of the cardiac pre- and after-load, these results suggest that the cardiac natriuretic peptides/GC-A signaling exerts its cardioprotective actions in both an endocrine and an autocrine/paracrine fashion. These mechanisms are schematically depicted in Fig. 1.


Figure 1.  ANP and BNP, the cardiac natriuretic peptides, protect the heart in not only an endocrine but also a paracrine fashion. Because ANP and BNP have potent diuretic, natriuretic and vasodilatory actions, augmentation of the ANP and BNP/GC-A signaling leads to a decrease in cardiac pre- and after-load, and their mobilization during cardiac failure is considered one of the compensatory mechanisms activated in response to heart damage. In addition to the hemodynamic effects of their actions as circulating hormones, recent evidence suggests that ANP and BNP also exert local cardioprotective effects by acting as autocrine/paracrine hormones.

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The molecular mechanism of GC-A-mediated inhibition of cardiac hypertrophy

To identify the molecular mechanism underlying cardiac hypertrophy seen in GC-A-deficient mice, DNA microarrays were used to identify genes upregulated in the hypertrophied heart [45]. Among several genes known to be upregulated in cardiac hypertrophy (e.g. α-skeletal actin, ANP and BNP), it has been found that the expression of the gene encoding myocyte-enriched calcineurin-interacting protein (MCIP1) is also increased. The MCIP1 gene is reportedly regulated by calcineurin, a critical regulator of cardiac hypertrophy. Thus, it was hypothesized that the calcineurin activity is enhanced in the heart of GC-A-deficient mice. To test this hypothesis, cultured neonatal cardiomyocytes were used to determine whether pharmacological inhibition of GC-A would increase calcineurin activity, which it did not [45]. On the other hand, stimulation of GC-A with ANP inhibited calcineurin activity, suggesting that it is by inhibiting the calcineurin pathway that cardiac GC-A signaling (activated by locally secreted natriuretic peptides) exerts its anti-hypertrophic effects. In fact, chronic treatment with FK506, which in combination with FK506-binding protein inhibits the phosphatase activity of calcineurin, significantly reduces the heart weight to body weight ratio, cardiomyocyte size and collagen volume fraction in GC-A-deficient mice compared with the wild-type mice [45]. A further study using microarray analysis and real-time PCR analysis revealed that, in addition to the calcineurin–nuclear factor of activated T-cells (NFAT) pathway, the calmodulin–CaMK–Hdac–Mef2 and PKC–MAPK–GATA4 pathways may also be involved in the cardiac hypertrophy seen in the GC-A-null mice [46].

Role of regulator of G-protein signaling in CG-A cardioprotective actions

Recently, it has been elegantly demonstrated that cGMP-dependent protein kinase (PKG) Iα attenuates signaling by the thrombin receptor protease-activated receptor (PAR) 1 through direct activation of regulator of G-protein signaling (RGS) 2 [47]. PKG-Iα binds directly to and phosphorylates RGS-2, which significantly increases the GTPase activity of Gαq, thereby terminating PAR-1 signaling. Given that cGMP is an intracellular second messenger for natriuretic peptides, RGS might mediate the cardioprotective effect of the GC-A signaling. To test this hypothesis, the role of RGS-4, which is the predominant RGS in cardiomyocytes under physiological conditions, was examined. In cultured cardiomyocytes, ANP stimulated the binding of PKG-Iα to RGS-4 as well as the phosphorylation of RGS-4 and its subsequent association with Gαq [48]. In addition, cardiomyocyte-specific overexpression of RGS-4 in GC-A-null mice significantly rescued the cardiac phenotype of these mice. On the contrary, overexpression of a dominant-negative form of RGS-4 blocked the inhibitory effects of ANP on cardiac hypertrophy [48]. Therefore, GC-A may activate cardiac RGS-4, which then inhibits the activity of Gαq and its downstream hypertrophic effectors. The endogenous cardioprotective mechanism meditated by ANP/BNP, GC-A and RGS-4 is depicted schematically in Fig. 2.


Figure 2.  Inhibitory mechanism of cardiac hypertrophy by the local natriuretic peptide system. Cardiac hypertrophy agonists such as angiotensin II, catecholamines and endothelins stimulate G-protein coupled receptor. Subsequent production of inositol triphosphate (IP3) promotes elevation of intracellular Ca2+ levels, which results in activation of the calcineurin/nuclear factor of activated T cells (NFAT) pathway. Cooperatively with the family of GATA transcription factors, NFAT activates the hypertrophic gene program, which includes the ANP- and BNP-coding genes. In an autocrine or paracrine fashion, ANP and BNP stimulate their receptor GC-A and exert their anti-hypertrophic actions via the activation of the RGS, which consequently results in an increase in the GTPase activity of the α subunit of the guanine nucleotide binding protein (Gαq) and in a decrease in the activity of the downstream signaling mediators (adapted from [48]).

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Very recently, PKG activation reflecting chronic inhibition of cGMP-selective phosphodiesterase 5 has been shown to suppress maladaptive cardiac hypertrophy by inhibiting Gαq-coupled stimulation, and the effect was not observed in mice lacking RGS-2 [49]. This suggests that RGS2 mediates the cardioprotective actions of PKG in pathological conditions such as pressure overload or excessive Gαq activation due to hypertrophic stimuli. In fact, RGS-2 is also implicated in the anti-hypertrophic action of cardiac GC-A [50].

The role of GC-A in myocardial infarction

It is well known that plasma levels of ANP and BNP are dramatically elevated early after myocardial infarction [51]. To examine the significance of this upregulation, experimental myocardial infarction by ligation of the left coronary artery was induced in mice lacking GC-A [52]. GC-A-deficient mice exhibited significantly higher mortality rate than wild-type mice, reflecting a higher incidence of acute heart failure. Four weeks after infarction, left ventricular remodeling, including myocardial hypertrophy and fibrosis, and impairment of the left ventricular systolic function were significantly more severe in mice lacking GC-A than in wild-type mice [52]. GC-A activation by endogenous cardiac natriuretic peptides may protect against acute heart failure and attenuate chronic cardiac remodeling after acute myocardial infarction.

Role of GC-A in peripheral arterial disease

A role of the natriuretic peptide system in peripheral arterial diseases has also been suggested. Activation of the natriuretic peptides–cGMP–PKG pathway was found to accelerate vascular regeneration and blood flow recovery in a murine model of peripheral arterial disease, in which leg ischemia was induced by femoral arterial ligation [53]. Recently, it has been reported that intraperitoneal injection of carperitide, a recombinant human ANP, accelerated blood flow recovery with increasing capillary density in the ischemic legs [54], indicating the role of exogenously administered ANP and BNP in angiogenesis. When the hindlimb ischemia model was performed in GC-A-deficient mice, autoamputation or ulcers were more severe in GC-A-deficient mice than in their wild-type counterparts [55]. Laser Doppler perfusion imaging revealed that the recovery of blood flow in the ischemic limb was significantly inhibited in GC-A-null mice compared with wild-type mice. In addition, vascular regeneration in response to critical hindlimb ischemia was severely impaired [55]. Similar attenuation of ischemic angiogenesis was observed in mice with conditional, endothelial-cell-restricted GC-A deletion. On the other hand, smooth-muscle-cell-restricted GC-A ablation did not affect ischemic neovascularization [56], suggesting that it is the endothelial GC-A that stimulates endothelial regeneration after induction of ischemia. Taken together, the evidence suggests that the natriuretic peptide pathway significantly contributes to peripheral vascular remodeling during ischemia.

Role of the CNP/GC-B pathway in bone formation

In a 1998 study, mice with transgenic overexpression of the BNP gene, especially those exhibiting high expression levels, unexpectedly displayed deformed bony skeletons characterized by kyphosis, elongated limbs and paws, and crooked tails, which resulted from a high turnover of endochondral ossification accompanied by overgrowth of the growth plate [57]. Even after crossing with GC-A-null mice, transgenic mice overexpressing BNP continued to exhibit marked longitudinal growth of the vertebrae and long bones [58]. Therefore, the effect of excess amount of BNP on endochondral ossification is independent of GC-A, and so signaling through another receptor was suggested.

In 2001, CNP-deficient mice were reported to show severe dwarfism as a result of impaired endochondral ossification [59], thus indicating that CNP acts locally as a positive regulator of endochondral ossification. In 2004, the phenotype of mice lacking GC-B was reported [60]. The GC-B-null animals exhibited dramatically impaired endochondral ossification and attenuation of longitudinal vertebral or limb bone growth. Therefore, it appears that GC-B is the receptor mediating the CNP action in inducing longitudinal bone growth. Furthermore, homozygous C-receptor-null mice also have skeletal deformities associated with a considerable increase in bone turnover [28], an opposite phenotype to that observed in the mice deficient for CNP. Since CNP is the only natriuretic peptide expressed in bone, it is suggested that one function of the C receptor is to clear locally synthesized CNP from bone and modulate its effects.

Since pharmacological amounts of BNP can stimulate GC-B, these results suggest that activation of the CNP/GC-B pathway in transgenic mice with elevated plasma concentrations of BNP or in mice lacking the C receptor for natriuretic peptides results in skeletal overgrowth. By contrast, inactivation of the CNP/GC-B pathway in mice lacking CNP, GC-B or cGMP-dependent protein kinase II (a downstream mediator of the CNP/GC-B pathway) results in dwarfism caused by defects in endochondral ossification.


  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References

As stated above, studies using genetically engineered animals revealed physiological and pathophysiological roles of the natriuretic peptides/receptor signaling pathways in the regulation of blood pressure/volume, maintenance of the cardiovascular system, and development of the longitudinal bone, acting as not only a circulating hormonal system but also a local regulatory system. Recent evidence also suggests roles for the natriuretic peptide system in renal [61] and neuronal [62] morphology and function. In addition, genetic defects of each component of the system in humans may cause diseases that are also observed in the genetically engineered animals. Furthermore, an interesting hypothesis that needs verification is that these observed phenomena could be the recapitulation of early developmental mechanisms. More studies at tissue, cellular and molecular levels are needed to clarify the mechanisms underlying the intriguing phenotypes observed in transgenic animal models. In addition, more studies at clinical and population levels are needed to elucidate the potential importance of the natriuretic peptide system in humans.


  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References

Our heartfelt appreciation goes to the late Dr Garbers, a former professor of the University of Texas, whose comments and suggestions were of inestimable value for our study using GC-A knockout mice, to Professor Misono of the University of Nevada School of Medicine, and to the reviewers of the FEBS Journal, whose comments significantly contributed to the writing of this review article.


  1. Top of page
  2. Abstract
  3. Natriuretic peptides
  4. Natriuretic peptide receptors
  5. Ligand selectivity
  6. Lessons from genetically engineered animals
  7. Summary
  8. Acknowledgements
  9. Disclosures
  10. References
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