腹主动脉瘤(AAA)是一种危及生命的血管疾病,但目前仍缺乏有效的治疗药物。最近,据报道,促红细胞生成素(EPO)在载脂蛋白E敲除(ApoE-/-)小鼠中诱导AAA形成,但有效的拮抗剂尚不清楚。在这项研究中,福莫特罗,β2肾上腺素能受体(β2AR)激动剂,被发现是抑制AAA的有前途的药物。为了检验这个假设,ApoE-/-小鼠用媒介物治疗,EPO,和EPO加上低,medium-,和高剂量福莫特罗,分别。AAA的发病率为0,55%,35%,10%,在这5组中有55%,分别。机械上,在体内和体外,EPO增加了血管平滑肌细胞(VSMC)的衰老,而中等剂量的福莫特罗减少了衰老,表现为衰老生物标志物的表达改变,包括H2AXserine139的磷酸化,衰老相关β-半乳糖苷酶活性,和P21蛋白水平。此外,在EPO诱导的AAA中,主动脉中沉默调节蛋白1(SIRT1)的表达降低,但中剂量福莫特罗显着升高。敲除β2AR和阻断环磷酸腺苷(cAMP)减弱福莫特罗在EPO诱导的VSMC衰老中的抑制作用。总之,中等剂量福莫特罗通过β2AR/cAMP/SIRT1途径减弱EPO诱导的AAA,这为治疗AAA提供了一种有前途的药物。
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease but effective drugs for treatment of AAA are still lacking. Recently, erythropoietin (EPO) is reported to induce AAA formation in apolipoprotein-E knock out (ApoE-/-) mice but an effective antagonist is unknown. In this study,
formoterol, a β2 adrenergic receptor (β2AR) agonist, is found to be a promising agent for inhibiting AAA. To test this hypothesis, ApoE-/- mice are treated with vehicle, EPO, and EPO plus low-, medium-, and high-dose
formoterol, respectively. The incidence of AAA is 0, 55%, 35%,10%, and 55% in these 5 groups, respectively. Mechanistically, senescence of vascular smooth muscle cell (VSMC) is increased by EPO while decreased by medium-dose
formoterol both in vivo and in vitro, manifested by the altered expression of senescence biomarkers including phosphorylation of H2AXserine139, senescence-associated β-galactosidase activity, and P21 protein level. In addition, expression of sirtuin 1 (SIRT1) in aorta is decreased in EPO-induced AAA but remarkably elevated by medium-dose
formoterol. Knockdown of β2AR and blockage of cyclic adenosine monophosphate (cAMP) attenuate the inhibitory role of formoterol in EPO-induced VSMC senescence. In summary, medium-dose
formoterol attenuates EPO-induced AAA via β2AR/cAMP/SIRT1 pathways, which provides a promising medication for the treatment of AAA.