Expression of Constitutively Active Guanylate Cyclase in Cardiomyocytes Inhibits the Hypertrophic Effects of Isoproterenol and Aortic Constriction on Mouse Hearts
| Autor: | Christian F. Deschepper, Ahmad Zahabi, Nadia Fortin, Sylvie Picard, Timothy L. Reudelhuber |
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| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.medical_specialty DNA Complementary Transgene Blood Pressure Mice Transgenic Biology Transfection Biochemistry Muscle hypertrophy Mice Atrial natriuretic peptide Internal medicine medicine Animals Tissue Distribution RNA Messenger Transgenes Receptor Cyclic GMP Molecular Biology Aorta Mice Knockout Mice Inbred C3H Myocardium Isoproterenol Hypertrophy Cell Biology Blotting Northern NPR1 NPR2 Protein Structure Tertiary Rats Mice Inbred C57BL Endocrinology Echocardiography Guanylate Cyclase COS Cells cardiovascular system Peptides Atrial natriuretic peptide receptor Receptors Atrial Natriuretic Factor Intracellular Adenylyl Cyclases |
| Zdroj: | Journal of Biological Chemistry. 278:47694-47699 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m309661200 |
| Popis: | Evidence from several rodent models has suggested that a reduction of either atrial natriuretic peptide or its receptor in the heart affects cardiac remodeling by promoting the onset of cardiac hypertrophy. The atrial natriuretic peptide receptor mediates signaling at least in part via the generation of intracellular cyclic GMP. To directly test whether accumulation of intracellular cyclic GMP conveys protection against cardiac hypertrophy, we engineered transgenic mice that overexpress a catalytic fragment of constitutively active guanylate cyclase domain of the atrial natriuretic peptide receptor in a cardiomyocyte-specific manner. Expression of the transgene increased the intracellular concentration of cyclic GMP specifically within cardiomyocytes and had no detectable effect on cardiac performance under basal conditions. However, expression of the transgene attenuated the effects of the pharmacologic hypertrophic agent isoproterenol on cardiac wall thickness and prevented the onset of the fetal gene expression program normally associated with cardiac hypertrophy. Likewise, expression of the transgene inhibited the hypertrophic effects of abdominal aortic constriction, since it abolished its effects on ventricular wall thickness and greatly attenuated its effects on cardiomyocyte size. Altogether, our results suggest that cyclic GMP is a cardioprotective agent against hypertrophy that acts via a direct local effect on cardiomyocytes. |
| Databáze: | OpenAIRE |
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