Hypervolemic hypertension in mice with systemic inactivation of the (floxed) guanylyl cyclase-A gene by alphaMHC-Cre-mediated recombination.

Abstract

To dissect the tissue-specific functions of atrial natriuretic peptide (ANP), we recently introduced loxP sites into the murine gene for its receptor, guanylyl cyclase-A (GC-A), by homologous recombination (tri-lox GC-A). For either smooth-muscle or cardiomyocyte-restricted deletion of GC-A, floxed GC-A mice were mated to transgenic mice expressing Cre-recombinase under the control of the smooth-muscle SM22 or the cardiac alphaMHC promoter. As shown in these studies, Cre-mediated recombination of the floxed GC-A gene fully inactivated GC-A function in a cell-restricted manner. In the present study we show that alphaMHC-Cre, but not SM22-Cre, with high frequency generates genomic recombinations of the floxed GC-A gene segments which were transmitted to the germline. Alleles with partial or complete deletions were readily recovered from the next generation, after segregation of the Cre-transgene. We took advantage of this strategy to generate a new mouse line with global, systemic deletion of GC-A. Doppler-echocardiographic and physiological studies in these mice demonstrate for the first time the tremendous impact of ANP/GC-A dysfunction on chronic blood volume homeostasis.

• Authors: Boris V Skryabin, Rita Holtwick, Larissa Fabritz, Markus N Kruse, Ilka Veltrup, Jörg Stypmann, Paulus Kirchhof, Karim Sabrane, Alexander Bubikat, Melanie Voss, Michaela Kuhn
• Journal: Genesis (New York, N.Y. : 2000) (Genesis) Vol. 39 Issue 4 Pg. 288-98 (Aug 2004) ISSN: 1526-954X [Print] United States
• PMID: 15287002 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2004 Wiley-Liss, Inc.

Chemical References

• DNA Primers
• Microfilament Proteins
• Muscle Proteins
• transgelin
• Atrial Natriuretic Factor
• Cre recombinase
• Integrases
• Myosin Heavy Chains
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Animals
• Atrial Natriuretic Factor (metabolism)
• Blood Pressure
• Blood Volume (genetics)
• Blotting, Southern
• DNA Primers
• Echocardiography, Doppler
• Gene Components
• Gene Silencing
• Guanylate Cyclase (genetics, metabolism)
• Heart (physiology)
• Hypertension (genetics)
• Integrases (metabolism)
• Mice
• Mice, Transgenic
• Microfilament Proteins (genetics)
• Models, Animal
• Muscle Proteins (genetics)
• Muscle, Smooth (metabolism)
• Myosin Heavy Chains (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Receptors, Atrial Natriuretic Factor (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction