AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1–3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1–3 in AAA by qRT-PCR (quantitative reverse transcription–PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14–4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76–2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37–12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.
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Research Article|
December 11 2013
Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2
Theophilus I. Emeto;
Theophilus I. Emeto
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Joseph V. Moxon;
Joseph V. Moxon
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Erik Biros;
Erik Biros
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Catherine M. Rush;
Catherine M. Rush
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
†Microbiology and Immunology, School of Veterinary and Biomedical Sciences, James Cook University, Townsville, QLD 4811, Australia
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Paula Clancy;
Paula Clancy
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Lynn Woodward;
Lynn Woodward
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Corey S. Moran;
Corey S. Moran
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Roby J. Jose;
Roby J. Jose
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Tam Nguyen;
Tam Nguyen
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
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Philip J. Walker;
Philip J. Walker
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
‡School of Medicine, Discipline of Surgery and Centre for Clinical Research, University of Queensland, and Department of Vascular Surgery, Royal Brisbane and Women's Hospital, Herston, QLD 4006, Australia
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Jonathan Golledge
*The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia
§Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, QLD 4814, Australia
Correspondence: Professor Jonathan Golledge (email jonathan.golledge@jcu.edu.au).
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Publisher: Portland Press Ltd
Received:
July 29 2013
Revision Received:
September 27 2013
Accepted:
October 10 2013
Accepted Manuscript online:
October 10 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 126 (7): 517–527.
Article history
Received:
July 29 2013
Revision Received:
September 27 2013
Accepted:
October 10 2013
Accepted Manuscript online:
October 10 2013
Citation
Theophilus I. Emeto, Joseph V. Moxon, Erik Biros, Catherine M. Rush, Paula Clancy, Lynn Woodward, Corey S. Moran, Roby J. Jose, Tam Nguyen, Philip J. Walker, Jonathan Golledge; Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2. Clin Sci (Lond) 1 April 2014; 126 (7): 517–527. doi: https://doi.org/10.1042/CS20130425
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