New players and new interactions within the natriuretic peptide system : mechanisms and pathophysiological consequences

Zhu, Xudong

Medicine
September 2012

Thesis or dissertation


Rights
© 2012 Xudong Zhu. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

The natriuretic peptide system plays a pivotal role in the regulation of cardiorenal homeostasis as well as in the pathogenesis of cardiovascular diseases. In this thesis, the biological effects of the newly designed natriuretic peptide (NP) ACNP and mechanisms of the interaction between natriuretic peptide receptor A (NPRA) and B (NPRB) are elucidated. The receptor profiles of different BNPs and degradation profile of hBNP1-42 are also investigated. ACNP stimulates both NPRA and NPRB and thus is more potent and effective compared to human ANP or CNP in stimulating cGMP in primary cells in vitro. In sham-operated mice, 4-week treatment with ACNP exerted similar potency in lowering blood pressure compared to that of ANP or CNP. However, ANP, but not ACNP, ameliorated the myocardial infarction-induced left ventricular dysfunction. The lack of benefit of ACNP might relate to its fast degradation by a still unknown enzyme in mouse serum. The interaction between NPRA and NPRB has been suggested since an impaired cGMP generation upon NP stimulation was observed in NPRA/NPRB co-transfected cells. The inhibitory effect of heterogeneous receptor complexes on natural NP/NPR/cGMP signalling were receptor dose-dependent. The attenuation of the CNP/NPRB/cGMP axis is caused by a blocked formation of NPRB mRNA by NPRA and thus decreasing NPRB quantity on the membrane. The attenuated ANP and BNP signalling may involve conformational changes within the NPRA/NPRB heterodimer, leading to less ligand accessibility or ligand-mediated activation of guanylyl cyclise (GC). Furthermore, different forms of BNP have been studied. The N-terminal truncated BNP (mBNP7-32) and the elongated BNP (mBNP1-45) are able to stimulate NPRA, whereas the C-terminal elongated hBNP1-42 is a poor activator of NPRA. Meanwhile, metabolism of hBNP1-42 on kidney membrane was different to that of lung membrane, suggesting specific peptidase(s) in the kidney being important for renal action of hBNP1-42. Taken together, this thesis gives novel insight into the new players and new interactions in the natriuretic peptide system. It provides potential mechanisms in receptor interplay leading to an impaired cGMP generation. It also opens new directions for the better understanding of cardiovascular diseases and may identify completely new treatment options.

Publisher
Hull York Medical School, The University of Hull and University of York
Supervisor
Walther, Thomas; Hardege, Jörg D.
Sponsor (Organisation)
China Scholarship Council; University of Hull
Qualification level
Doctoral
Qualification name
PhD
Language
English
Extent
10 MB
Identifier
hull:14364
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