Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B.
Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-BDeltaKC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP- but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-BDeltaKC expression selectively reduced NPR-B but not NPR-A signaling. NPR-BDeltaKC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany. langenit@mail.nih.gov
Thomas H
TH
Langenickel
Jens
J
Buttgereit
Ines
I
Pagel-Langenickel
Maren
M
Lindner
Jan
J
Monti
Knut
K
Beuerlein
Nidal
N
Al-Saadi
Ralph
R
Plehm
Elena
E
Popova
Jens
J
Tank
Rainer
R
Dietz
Roland
R
Willenbrock
Michael
M
Bader
D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000235:genetics; D001846:Bone Development / Q000235:genetics; D006152:Cyclic GMP / Q000378:metabolism; D005799:Genes, Dominant; D006162:Guanylate Cyclase / Q000235:genetics*; D006339:Heart Rate / Q000235:genetics; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000502:physiology; D009154:Mutation; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D017384:Sequence Deletion; D000099242:Atrial Natriuretic Factor Receptor B
D006152:Cyclic GMP; D006162:Guanylate Cyclase; D020098:Natriuretic Peptide, C-Type; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B; C091715:atrial natriuretic factor receptor A