Local atrial natriuretic peptide signaling prevents hypertensive cardiac hypertrophy in endothelial nitric-oxide synthase-deficient mice
| Autor: | Axel Gödecke, Bernd Zetsche, Dominik Eckardt, Larissa Fabritz, Hideo Baba, Alexander Bubikat, Leon J. De Windt, Heidrun Sickler, Michaela Kuhn |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Genotype Nitric Oxide Synthase Type III Heart Ventricles Blotting Western Medizin Nitric Oxide Synthase Type II Blood Pressure Mice Transgenic Biology Biochemistry Muscle hypertrophy Mice Atrial natriuretic peptide Internal medicine medicine Animals RNA Messenger Phosphorylation Cyclic GMP Molecular Biology Mice Knockout Myocardium Cardiac myocyte Hypertrophy Cell Biology Blotting Northern medicine.disease Hypertensive heart disease Calcineurin Phenotype Endocrinology Blood pressure Hypertension cardiovascular system Nitric Oxide Synthase Atrial Natriuretic Factor Gene Deletion Signal Transduction |
| Popis: | 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. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Databáze: | OpenAIRE |
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