Hypervolemic hypertension in mice with systemic inactivation of the (floxed) guanylyl cyclase-A gene by alphaMHC-Cre-mediated recombination.
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.
Skryabin
Boris V
BV
Institute of Experimental Pathology, Universitätsklinikum Münster, Münster, Germany.
Holtwick
Rita
R
Fabritz
Larissa
L
Kruse
Markus N
MN
Veltrup
Ilka
I
Stypmann
Jörg
J
Kirchhof
Paulus
P
Sabrane
Karim
K
Bubikat
Alexander
A
Voss
Melanie
M
Kuhn
Michaela
M
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001794:Blood Pressure; D001810:Blood Volume / Q000235:genetics*; D015139:Blotting, Southern; D017931:DNA Primers; D015150:Echocardiography, Doppler; D040461:Gene Components; D020868:Gene Silencing; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D006973:Hypertension / Q000235:genetics*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D023421:Models, Animal; D009124:Muscle Proteins / Q000235:genetics; D009130:Muscle, Smooth / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D008840:Microfilament Proteins; D009124:Muscle Proteins; C051615:transgelin; D009320:Atrial Natriuretic Factor; C045073:Cre recombinase; D019426:Integrases; D018995:Myosin Heavy Chains; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A