Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm.
Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm.
复制标题
DOI：
10.1073/pnas.1717906115
复制
发表时间：
2018-02-20
影响因子：
11.1
通讯作者：
Haeggström JZ
中科院分区：
文献类型：
--
作者：
Di Gennaro A;Araújo AC;Busch A;Jin H;Wågsäter D;Vorkapic E;Caidahl K;Eriksson P;Samuelsson B;Maegdefessel L;Haeggström JZ
半胱氨酰-白三烯（cys-LT）是与人类炎症性疾病，特别是哮喘有关的脂质介质。我们以前已经确定了cys-LT在人类腹主动脉瘤（AAA）的组织标本，并联系这些介质增加金属蛋白酶的活性。在这里，我们表明，在体内拮抗CysLT 1受体的孟鲁司特，一个既定的抗哮喘药物，防止动脉瘤在三个小鼠模型的AAA在剂量相当于人类的医疗实践。总之，这些数据支持cys-LT在AAA中的作用，并表明治疗这种临床沉默和高致死性疾病的新的潜在治疗方法。半胱氨酰-白三烯（cys-LT）是5-脂氧合酶衍生的脂质介质，参与炎症性疾病，特别是哮喘的发病机制和进展。我们以前发现的证据表明，这些介质的人腹主动脉瘤（AAA）的组织标本中的蛋白水解酶水平的增加。在这里，我们发现，孟鲁司特（一种已确立的抗哮喘药物）对CysLT 1受体的拮抗作用，在与人类医疗实践相当的剂量下，可在CaCl 2诱导的AAA小鼠模型中防止强烈的主动脉扩张（增加>50%=动脉瘤）。组织提取物的分析显示，孟鲁司特降低了主动脉壁中基质金属蛋白酶-9（MMP-9）和巨噬细胞炎性蛋白-1 α（MIP-1α）的水平。此外，动脉瘤进展是通过CysLT 1信号传导特异性介导的，因为选择性CysLT 2拮抗剂没有作用。当在动脉瘤诱导后几天开始使用孟鲁司特治疗时，也观察到血管扩张显著减少，这表明该药物不仅可以预防，而且可以停止并可能逆转已经进行的退行性过程。此外，在另外两个独立模型中，孟鲁司特降低了主动脉破裂的发生率并减弱了AAA的发展，即，血管紧张素II和猪胰弹性蛋白酶诱导的AAA。我们的结果表明，cys-LT参与AAA的发病机制，并且CysLT 1受体的拮抗作用是预防和治疗这种临床上无症状且高度致命的疾病的一种有前途的策略。
Cysteinyl-leukotrienes (cys-LTs) are lipid mediators involved in human inflammatory diseases, in particular asthma. We have previously identified cys-LTs in tissue specimens of human abdominal aortic aneurysm (AAA) and linked these mediators to increased metalloproteinase activity. Here we show in vivo that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against aneurysm in three mouse models of AAA at doses comparable to human medical practice. Together, these data support the role of cys-LTs in AAA and indicate a new potential therapeutic approach for treatment of this clinically silent and highly lethal disease. Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1α (MIP-1α) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.
登录
查看更多内容
影响因子：
15.9
作者：
Longo, GM;Xiong, WF;Baxter, BT
通讯作者：
Baxter, BT
DOI：
10.1161/atvbaha.115.306497
发表时间：
2016-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Liu CL;Wemmelund H;Wang Y;Liao M;Lindholt JS;Johnsen SP;Vestergaard H;Fernandes C;Sukhova GK;Cheng X;Zhang JY;Yang C;Huang X;Daugherty A;Levy BD;Libby P;Shi GP
通讯作者：
Shi GP
DOI：
10.1161/atvbaha.114.304016
发表时间：
2014-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Bhamidipati CM;Whatling CA;Mehta GS;Meher AK;Hajzus VA;Su G;Salmon M;Upchurch GR Jr;Owens GK;Ailawadi G
通讯作者：
Ailawadi G
影响因子：
5.3
作者：
Kristo, Fjoralba;Hardy, Gregory J.;Anderson, Thomas J. T.;Sinha, Sumita;Ahluwalia, Neil;Lin, Alexander Y.;Passeri, Jonathan;Scherrer-Crosbie, Marielle;Gerszten, Robert E.
通讯作者：
Gerszten, Robert E.
DOI：
10.1016/j.prostaglandins.2007.03.005
发表时间：
2007-08-01
影响因子：
2.9
作者：
Cao, Richard Yang;Adams, Michael A.;Funk, Colin D.
通讯作者：
Funk, Colin D.