Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2
Urocortin 2 is associated with abdominal aortic aneurysm and mediates anti-proliferative effects on vascular smooth muscle cells via corticotrophin releasing factor receptor 2
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DOI：
10.1042/cs20130425
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发表时间：
2014-04-01
期刊：
影响因子：
6
通讯作者：
Golledge, Jonathan
中科院分区：
文献类型：
--
作者：
Emeto, Theophilus I.;Moxon, Joseph V.;Golledge, Jonathan
腹主动脉瘤（AAA）是老年人猝死的重要原因，但目前尚无有效的药物治疗。UCN（urocortins 1 -3）及其受体CRFR（corticotrophin releasing factor receptor）-1和-2与多种CVD（心血管疾病）有关。我们通过qRT-PCR（定量逆转录PCR）和ELISA评估UCN 1 -3在AAA中的相对表达，并在体外检测UCN 2如何影响人主动脉VSMC（血管平滑肌细胞）Akt磷酸化、促炎细胞因子IL（白细胞介素）-6分泌、增殖、细胞周期和凋亡。UCN 2和CRFR 2表达在AAA体活检中显著上调。AAA体活检在体外释放了大量的UCN 2。AAA患者的中位血浆UCN 2浓度为2.20 ng/ml（四分位数范围1.14-4.55 ng/ml，n=67），非囊性PAD（外周动脉疾病）患者的中位血浆UCN 2浓度为1.11 ng/ml（四分位数范围0.76-2.55 ng/ml，n = 67）（P = 0.001）。UCN 2在最高四分位数的患者AM的患病率是其他风险因素的4.12倍（95%置信区间，1.37-12.40），P = 0.012。在体外，UCN 2以剂量依赖性方式显著抑制VSMC Akt磷酸化和增殖。UCN 2诱导VSMC G（1）细胞周期阻滞，并在24 h内增加IL-6的分泌。CRFR 2拮抗剂astressin-2B显著消除了UCN 2对VSMC的作用。总之，UCN 2与AAA显著相关，并通过诱导G1期细胞周期阻滞抑制VSMC增殖，这表明在AAA发病机制中具有合理的调节作用。
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 AM 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 G(1) 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.