Abstract
The crucial functions of atrial natriuretic peptide (ANP) and endothelial nitric oxide/NO in the regulation of arterial blood pressure have been emphasized by the hypertensive phenotype of mice with systemic inactivation of either the guanylyl cyclase-A receptor for ANP (GC-A-/-) or endothelial nitric-oxide synthase (eNOS-/-). Intriguingly, similar levels of arterial hypertension are accompanied by marked cardiac hypertrophy in GC-A-/-, but not in eNOS-/-, mice, suggesting that changes in local pathways regulating cardiac growth accelerate cardiac hypertrophy in the former and protect the heart of the latter. Our recent observations in mice with conditional, cardiomyocyte-restricted GC-A deletion demonstrated that ANP locally inhibits cardiomyocyte growth. Abolition of these local, protective effects may enhance the cardiac hypertrophic response of GC-A-/- mice to persistent increases in hemodynamic load. Notably, eNOS-/- mice exhibit markedly increased cardiac ANP levels, suggesting that increased activation of cardiac GC-A can prevent hypertensive heart disease. To test this hypothesis, we generated mice with systemic inactivation of eNOS and cardiomyocyte-restricted deletion of GC-A by crossing eNOS-/- and cardiomyocyte-restricted GC-A-deficient mice. Cardiac deletion of GC-A did not affect arterial hypertension but significantly exacerbated cardiac hypertrophy and fibrosis in eNOS-/- mice. This was accompanied by marked cardiac activation of both the mitogen-activated protein kinase (MAPK) ERK 1/2 and the phosphatase calcineurin. Our observations suggest that local ANP/GC-A/cyclic GMP signaling counter-regulates MAPK/ERK- and calcineurin/nuclear factor of activated T cells-dependent pathways of cardiac myocyte growth in hypertensive eNOS-/- mice.
Original language | English |
---|---|
Pages (from-to) | 21594-9 |
Number of pages | 6 |
Journal | Journal of Biological Chemistry |
Volume | 280 |
Issue number | 22 |
DOIs | |
Publication status | Published - 3 Jun 2005 |
Keywords
- Animals
- Atrial Natriuretic Factor
- Blood Pressure
- Blotting, Northern
- Blotting, Western
- Cyclic GMP
- Gene Deletion
- Genotype
- Heart Ventricles
- Hypertension
- Hypertrophy
- Mice
- Mice, Knockout
- Mice, Transgenic
- Myocardium
- Nitric Oxide Synthase
- Nitric Oxide Synthase Type II
- Nitric Oxide Synthase Type III
- Phenotype
- Phosphorylation
- RNA, Messenger
- Signal Transduction