Emeto, Theophilus I., Moxon, Joseph V., Biros, Erik, Rush, Catherine M., Clancy, Paula, Woodward, Lynn, Moran, Corey S., Jose, Roby J., Nguyen, Tan, Walker, Philip J., and Golledge, Jonathan (2014) Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2. Clinical Science, 126 (7). pp. 517-527.

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Abstract

Abdominal aortic aneurysm (AAA) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The urocortins (UCN1-3) and their receptors; corticotrophin releasing factor receptor-1 and -2 (CRFR1 and 2) have been implicated in various cardiovascular diseases. We assessed the relative expression of UCN1-3 in AAA by qPCR and ELISA, and examined in vitro how UCN2 affects human aortic vascular smooth muscle cell (VSMC) Akt phosphorylation, pro-inflammatory cytokine interleukin 6 (IL-6) secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly upregulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations was 0.52 nmol/L in AAA patients (inter-quartile range 0.27-1.10, n=67) and 0.26 nmol/L in patients with non-aneurysmal peripheral artery disease (PAD, inter-quartile range 0.18-0.53, n=67), P=0.001. Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence intervals 0.32-2.91) 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 VSMC. 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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