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Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Item Type:Article
Title:Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B
Creators Name:Langenickel, T.H. and Buttgereit, J. and Pagel-Langenickel, I. and Lindner, M. and Monti, J. and Beuerlein, K. and Al-Saadi, N. and Plehm, R. and Popova, E. and Tank, J. and Dietz, R. and Willenbrock, R. and Bader, M.
Abstract: 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.
Keywords:C-type Natriuretic Peptide, Knockdown, Animals, Rats
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:103
Number:12
Page Range:4735-4740
Date:21 March 2006
Official Publication:https://doi.org/10.1073/pnas.0510019103
PubMed:View item in PubMed

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