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Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart.

Kishimoto I, Tokudome T, Horio T, Garbers DL, Nakao K, Kangawa K - Curr Cardiol Rev (2009)

Bottom Line: These results suggest that the actions of a local cardiac ANP/BNP-GC-A system are essential for maintenance of normal cardiac architecture.In addition, GC-A was shown to exert its cardioprotective effects by inhibiting angiotensin II-induced hypertrophic signaling, and recent evidence suggests that regulator of G protein signaling (RGS) subtype 4 is involved in the GC-A-mediated inhibition of Galphaq-coupled hypertrophic signal transduction.Furthermore, several different groups have reported that functional mutations in the promoter region of the human GC-A gene are associated with essential hypertension and ventricular hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: National Cardiovascular Center, Research Institute 5-7-1 Fujishiro-dai Suita City Osaka 565-8565, Japan.

ABSTRACT
Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones, secretions of which are markedly upregulated during cardiac failure, making their plasma levels clinically useful diagnostic markers. ANP and BNP exert potent diuretic, natriuretic and vasorelaxant effects, which are mediated via their common receptor, guanylyl cyclase (GC)-A (also called natriuretic peptide receptor (NPR)-A). Mice deficient for GC-A are mildly hypertensive and show marked cardiac hypertrophy and fibrosis that is disproportionately severe, given their modestly higher blood pressure. Indeed, the cardiac hypertrophy seen in these mice is enhanced in a blood pressure-independent manner and is suppressed by cardiomyocyte-specific overexpression of GC-A. These results suggest that the actions of a local cardiac ANP/BNP-GC-A system are essential for maintenance of normal cardiac architecture. In addition, GC-A was shown to exert its cardioprotective effects by inhibiting angiotensin II-induced hypertrophic signaling, and recent evidence suggests that regulator of G protein signaling (RGS) subtype 4 is involved in the GC-A-mediated inhibition of Galphaq-coupled hypertrophic signal transduction. Furthermore, several different groups have reported that functional mutations in the promoter region of the human GC-A gene are associated with essential hypertension and ventricular hypertrophy. These findings suggest that endogenous GC-A protects the heart from pathological hypertrophic stimuli, and that humans who express only low levels of GC-A are genetically predisposed to cardiac remodeling and hypertension.

No MeSH data available.


Related in: MedlinePlus

Transcriptional activities of the indicated (CT)n and 8-bp deletion reporter constructs in human aortic smooth muscle cells. Shown are the mean firefly (Luc)/renilla luciferase activity ratios. Note that the GC-A promoter containing (CT)n=6 or the 8bp deletion drove significantly less transcriptional activity than the promoter containing (CT)n=10. Modified from reference [34].
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Figure 5: Transcriptional activities of the indicated (CT)n and 8-bp deletion reporter constructs in human aortic smooth muscle cells. Shown are the mean firefly (Luc)/renilla luciferase activity ratios. Note that the GC-A promoter containing (CT)n=6 or the 8bp deletion drove significantly less transcriptional activity than the promoter containing (CT)n=10. Modified from reference [34].

Mentions: We also examined the association between polymorphisms within the GC-A promoter and essential hypertension in a group of Japanese subjects (177 hypertensive and 170 normotensive) and identified five allele types in which 6, 9, 10, 11 or12 CT dinucleotide repeats around position -293, upstream of the ATG codon [34]. The frequency of the (CT)n=6 allele was significantly higher among hypertensive subjects than among normotensive ones, while the frequencies of the other four allele types did not differ between the two groups. Promoter-reporter analyses carried out in cultured human aortic smooth muscle cells using a luciferase gene fused to the 5'-flanking region of the GC-A gene revealed that, like the promoter containing an 8bp deletion at position -60, the promoter containing (CT)n=6 at position -293 drove less transcriptional activity than the promoter containing (CT)n=10 (control) (Fig. (5)). Our results thus define the (CT)n polymorphism in the GC-A promoter as a potent and novel hypertension susceptibility marker. Although it did not reach statistical significance, preliminary data indicate that the incidence of left ventricular hypertrophy tends to be higher among patients carrying the (CT)n=6 allele than among those carrying other alleles.


Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart.

Kishimoto I, Tokudome T, Horio T, Garbers DL, Nakao K, Kangawa K - Curr Cardiol Rev (2009)

Transcriptional activities of the indicated (CT)n and 8-bp deletion reporter constructs in human aortic smooth muscle cells. Shown are the mean firefly (Luc)/renilla luciferase activity ratios. Note that the GC-A promoter containing (CT)n=6 or the 8bp deletion drove significantly less transcriptional activity than the promoter containing (CT)n=10. Modified from reference [34].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803288&req=5

Figure 5: Transcriptional activities of the indicated (CT)n and 8-bp deletion reporter constructs in human aortic smooth muscle cells. Shown are the mean firefly (Luc)/renilla luciferase activity ratios. Note that the GC-A promoter containing (CT)n=6 or the 8bp deletion drove significantly less transcriptional activity than the promoter containing (CT)n=10. Modified from reference [34].
Mentions: We also examined the association between polymorphisms within the GC-A promoter and essential hypertension in a group of Japanese subjects (177 hypertensive and 170 normotensive) and identified five allele types in which 6, 9, 10, 11 or12 CT dinucleotide repeats around position -293, upstream of the ATG codon [34]. The frequency of the (CT)n=6 allele was significantly higher among hypertensive subjects than among normotensive ones, while the frequencies of the other four allele types did not differ between the two groups. Promoter-reporter analyses carried out in cultured human aortic smooth muscle cells using a luciferase gene fused to the 5'-flanking region of the GC-A gene revealed that, like the promoter containing an 8bp deletion at position -60, the promoter containing (CT)n=6 at position -293 drove less transcriptional activity than the promoter containing (CT)n=10 (control) (Fig. (5)). Our results thus define the (CT)n polymorphism in the GC-A promoter as a potent and novel hypertension susceptibility marker. Although it did not reach statistical significance, preliminary data indicate that the incidence of left ventricular hypertrophy tends to be higher among patients carrying the (CT)n=6 allele than among those carrying other alleles.

Bottom Line: These results suggest that the actions of a local cardiac ANP/BNP-GC-A system are essential for maintenance of normal cardiac architecture.In addition, GC-A was shown to exert its cardioprotective effects by inhibiting angiotensin II-induced hypertrophic signaling, and recent evidence suggests that regulator of G protein signaling (RGS) subtype 4 is involved in the GC-A-mediated inhibition of Galphaq-coupled hypertrophic signal transduction.Furthermore, several different groups have reported that functional mutations in the promoter region of the human GC-A gene are associated with essential hypertension and ventricular hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: National Cardiovascular Center, Research Institute 5-7-1 Fujishiro-dai Suita City Osaka 565-8565, Japan.

ABSTRACT
Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones, secretions of which are markedly upregulated during cardiac failure, making their plasma levels clinically useful diagnostic markers. ANP and BNP exert potent diuretic, natriuretic and vasorelaxant effects, which are mediated via their common receptor, guanylyl cyclase (GC)-A (also called natriuretic peptide receptor (NPR)-A). Mice deficient for GC-A are mildly hypertensive and show marked cardiac hypertrophy and fibrosis that is disproportionately severe, given their modestly higher blood pressure. Indeed, the cardiac hypertrophy seen in these mice is enhanced in a blood pressure-independent manner and is suppressed by cardiomyocyte-specific overexpression of GC-A. These results suggest that the actions of a local cardiac ANP/BNP-GC-A system are essential for maintenance of normal cardiac architecture. In addition, GC-A was shown to exert its cardioprotective effects by inhibiting angiotensin II-induced hypertrophic signaling, and recent evidence suggests that regulator of G protein signaling (RGS) subtype 4 is involved in the GC-A-mediated inhibition of Galphaq-coupled hypertrophic signal transduction. Furthermore, several different groups have reported that functional mutations in the promoter region of the human GC-A gene are associated with essential hypertension and ventricular hypertrophy. These findings suggest that endogenous GC-A protects the heart from pathological hypertrophic stimuli, and that humans who express only low levels of GC-A are genetically predisposed to cardiac remodeling and hypertension.

No MeSH data available.


Related in: MedlinePlus