Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2

Abstract

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.

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Interestingly, UCN3 gene expression was downregulated in the suprarenal region of the aorta (susceptive to aneurysm formation in mice) compared to the infrarenal region (resistant to aneurysm formation in mice) [102], raising the speculation that UCNs have a protective function against AAA. In another study, the same group reported that UCN2 and CRFR2 gene expression were significantly higher in the most dilated part of the human AAA compared to the non-dilated proximal neck of the AAA [101]. Moreover, in a well-controlled cohort they also documented that UCN2 plasma level was higher in AAA patients compared to non-aneurysmal patients [89].…”

“…Others reported that UCN1 treatment inhibited cell proliferation and VEGF release in rat smooth muscle cells [104]. Accordingly, UCN2 decreased human vascular smooth muscle proliferation and increases IL-6 secretion in a dependent manner of CRFR2 [101]. Taken together these data indicate that UNCs modulate critical molecular pathways of AAA pathophysiology in a protective manner; however, the speculation about the potential of UNCs against AAA must be evaluated in future studies.…”

“…Moreover, in a well-controlled cohort they also documented that UCN2 plasma level was higher in AAA patients compared to non-aneurysmal patients [89]. Interestingly, UCN2 protein expression within the AAA wall was mostly co-located with infiltrating Tlymphocytes and neutrophils [101], suggesting that these infiltrated immune cells are the source of UCN2 production within the AAA wall. In keeping with that, it was observed that explant preparation from the dilated portion of AAA releases larger amount of UCN2 compared to non-dilated proximal neck of the AAA [101].…”

“…Various studies in humans and animals have shown the implication of UCNs in different cardiovascular disorders, such as atherosclerosis, myocardial infarct and heart failure [97,99,100]; however, its role on AAA has only been reported very recently [101,102]. The first evidence associating the UCNs to AAA was documented by Rush et al [102].…”

“…Interestingly, UCN2 protein expression within the AAA wall was mostly co-located with infiltrating Tlymphocytes and neutrophils [101], suggesting that these infiltrated immune cells are the source of UCN2 production within the AAA wall. In keeping with that, it was observed that explant preparation from the dilated portion of AAA releases larger amount of UCN2 compared to non-dilated proximal neck of the AAA [101]. These data demonstrate that UCN2 has a plausive role on AAA pathogenesis; however, do not provide information about its function, if beneficial or detrimental.…”