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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

Cardiac Hypertrophy in GC-A KO. GC-A-deficient mice (GC-A KO) develop cardiac hypertrophy, as shown on the right.
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Figure 2: Cardiac Hypertrophy in GC-A KO. GC-A-deficient mice (GC-A KO) develop cardiac hypertrophy, as shown on the right.

Mentions: Because ANP and BNP share a common receptor (i.e., GC-A), the absence of one peptide can presumably be compensated for by the other. Therefore, to reveal the full effects of cardiac natriuretic peptide signaling, we generated mice that lacked endogenous GC-A (GC-A KO), and analyzed the cardiovascular phenotype [14-16]. As shown in Figs. (2 and 3), targeted deletion of the GC-A gene resulted in marked cardiac hypertrophy and fibrosis. Although GC-A KO mice also display mild hypertension, the cardiac hypertrophy was disproportionately severe, given the modest rise in blood pressure of the animal. In fact, other animal models that show similar increases in blood pressure do not exhibit the same degree of hypertrophy as GC-A KO mice [17, 18].


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)

Cardiac Hypertrophy in GC-A KO. GC-A-deficient mice (GC-A KO) develop cardiac hypertrophy, as shown on the right.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Cardiac Hypertrophy in GC-A KO. GC-A-deficient mice (GC-A KO) develop cardiac hypertrophy, as shown on the right.
Mentions: Because ANP and BNP share a common receptor (i.e., GC-A), the absence of one peptide can presumably be compensated for by the other. Therefore, to reveal the full effects of cardiac natriuretic peptide signaling, we generated mice that lacked endogenous GC-A (GC-A KO), and analyzed the cardiovascular phenotype [14-16]. As shown in Figs. (2 and 3), targeted deletion of the GC-A gene resulted in marked cardiac hypertrophy and fibrosis. Although GC-A KO mice also display mild hypertension, the cardiac hypertrophy was disproportionately severe, given the modest rise in blood pressure of the animal. In fact, other animal models that show similar increases in blood pressure do not exhibit the same degree of hypertrophy as GC-A KO mice [17, 18].

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