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Characterisation of the anti-inflammatory and anti-proliferative effects of natriuretic peptides in rodents.

Panayiotou, C.M.; (2007) Characterisation of the anti-inflammatory and anti-proliferative effects of natriuretic peptides in rodents. Doctoral thesis , University of London. Green open access

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Natriuretic peptides are a family of vasoactive hormones that play important roles in cardiovascular homeostasis. These peptides exert biological effects primarily via activation of guanylate cyclase (GC)-coupled natriuretic peptide receptors (NPR) that generate the intracellular messenger cyclic guanosine 3',5'-monophosphate (cGMP). Activation of the cytosolic GC by NO is well-established to mediate cGMP-dependent, anti-atherogenic effects however, an analogous cytoprotective role for natriuretic peptides has yet to be fully elucidated. Since many cardiovascular disorders (e.g. atherosclerosis, septic shock) are now accepted as inflammation-based diseases, identification of potential roles for natriuretic peptides in regulating vascular inflammation might assist in the prevention and treatment of cardiovascular pathology. The studies described in this thesis investigated the hypothesis that natriuretic peptides (i.e. atrial natriuretic peptide ANP , C-type natriuretic peptide CNP ) affect pro-inflammatory protein expression (i.e. inducible NO synthase, iNOS) and cell proliferation via activation of GC-linked NPR. Herein, it is demonstrated that in NPR-A knockout mice, iNOS expression and NO production in response to intravenous administration of bacterial lipopolysaccharide is significantly reduced compared to wild-type controls this difference is mirrored in the ex vivo functional reactivity of vessels from such animals. However, neither ANP nor CNP were able to alter iNOS expression or NO production in vitro in RAW264.7 murine macrophages or primary rat aortic smooth muscle cells. CNP, but not ANP, transiently enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2. CNP-induced ERK 1/2 phosphorylation was blocked by the selective ERK 1/2 inhibitor PD98059, the Gj-protein inhibitor Pertussis toxin, and the selective NPR-C antagonist M372049. Accordingly, CNP inhibited vascular smooth muscle proliferation in a PD98059- and M372049-reversible manner. These observations suggest that part of the anti-atherogenic profile of CNP is mediated via NPR-C, Gi-dependent ERK 1/2 phosphorylation and inhibition of vascular smooth muscle proliferation. Moreover, my findings identify a potential pro-inflammatory role for ANP/NPR-A-dependent signalling in vivo.

Type: Thesis (Doctoral)
Title: Characterisation of the anti-inflammatory and anti-proliferative effects of natriuretic peptides in rodents.
Identifier: PQ ETD:592377
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/1445064
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