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

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.

• Authors: Thomas H Langenickel, Jens Buttgereit, Ines Pagel-Langenickel, Maren Lindner, Jan Monti, Knut Beuerlein, Nidal Al-Saadi, Ralph Plehm, Elena Popova, Jens Tank, Rainer Dietz, Roland Willenbrock, Michael Bader
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 12 Pg. 4735-40 (Mar 21 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16537417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Natriuretic Peptide, C-Type
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A
• atrial natriuretic factor receptor B
• Cyclic GMP

Topics

• Animals
• Animals, Genetically Modified
• Blood Pressure (genetics)
• Bone Development (genetics)
• Cyclic GMP (metabolism)
• Genes, Dominant
• Guanylate Cyclase (genetics)
• Heart Rate (genetics)
• Heart Ventricles (drug effects, pathology, physiopathology)
• Hypertrophy, Left Ventricular (genetics, pathology, physiopathology)
• Kidney (physiology)
• Mutation
• Natriuretic Peptide, C-Type (pharmacology)
• Rats
• Receptors, Atrial Natriuretic Factor (genetics)
• Sequence Deletion