Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation.
Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation.
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DOI：
10.1371/journal.pone.0072558
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shimokawa H
中科院分区：
文献类型：
--
作者：
Takahashi K;Matsumoto Y;Do e Z;Kanazawa M;Satoh K;Shimizu T;Sato A;Fukumoto Y;Shimokawa H
腹主动脉瘤（AAA）是一种危及生命的血管疾病。他汀类药物和钙通道阻滞剂（CCBs）是否对AAA的扩张有抑制作用仍存在争议。一些研究报道CCBs对Rho激酶活性具有抑制作用。Rho激酶在多种心血管疾病的发病机制中起重要作用。然而，没有研究报道Rho激酶和人AAAs之间的关联。实验性AAA诱导载脂蛋白E-缺陷（ApoE-/-）小鼠血管紧张素II（AngII）输注28天。将其随机分为以下5组：单独输注生理盐水（假手术）、单独输注AngII、AngII输注+阿托伐他汀（10 mg/kg/天）、AngII输注+阿托伐他汀（1 mg/kg/天）和AngII输注+阿托伐他汀（10 mg/kg/天）和阿托伐他汀（1 mg/kg/天）联合治疗。与假手术组相比，联合治疗显著抑制了AngII诱导的最大主动脉直径增加，而每种单药治疗均无抑制作用。联合治疗显著减少了血管紧张素II诱导的细胞凋亡和弹性蛋白降解在AAA病变，而每一个单一疗法没有。此外，Rho-激酶活性，评估肌球蛋白结合亚基（底物Rho-激酶）和基质金属蛋白酶活性的磷酸化程度显着增加，在血管紧张素II诱导的AAA病变与假手术相比，这两个再次显着抑制联合治疗。在人腹主动脉标本中，与对照组相比，AAA病变组Rho激酶的活性和表达均上调。Rho激酶在人AAA的主动脉壁中上调。联合治疗与阿托伐他汀，但不是每一个单一疗法，抑制血管紧张素II诱导的AAA形成在小鼠体内，其中Rho激酶抑制可能参与。
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. Experimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.
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影响因子：
20.1
作者：
Das R;Burke T;Van Wagoner DR;Plow EF
通讯作者：
Plow EF
影响因子：
3.7
作者：
Ghoshal S;Loftin CD
通讯作者：
Loftin CD
影响因子：
15.9
作者：
Bruemmer, D;Collins, AR;Hsueh, WA
通讯作者：
Hsueh, WA
影响因子：
37.8
作者：
Matsumoto, Yasuharu;Adams, Volker;Linke, Axel
通讯作者：
Linke, Axel
DOI：
10.1016/j.jamcollsurg.2009.03.005
发表时间：
2009-07-01
影响因子：
5.2
作者：
Feeney, James M.;Burns, Karyl;Jacobs, Lenworth M.
通讯作者：
Jacobs, Lenworth M.