Pravastatin activates activator protein 2 alpha to augment the angiotensin II-induced abdominal aortic aneurysms.
Pravastatin activates activator protein 2 alpha to augment the angiotensin II-induced abdominal aortic aneurysms.
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普伐他汀激活激活蛋白 2 α 以增强血管紧张素 II 诱导的腹主动脉瘤
DOI：
10.18632/oncotarget.15104
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发表时间：
2017-02-28
期刊：
影响因子：
--
通讯作者：
Wang SX
中科院分区：
文献类型：
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作者：
Ma H;Liang WJ;Shan MR;Wang XQ;Zhou SN;Chen Y;Guo T;Li P;Yu HY;Liu C;Yin YL;Wang YL;Dong B;Pang XY;Wang SX
我们以前曾报道过，尼古丁或血管紧张素II（AngII）激活AMP激活激酶α 2（AMPKa 2）可诱发Apoe−/−小鼠腹主动脉瘤（AAA）的形成。他汀类药物广泛应用于高脂血症的治疗，它能激活血管细胞中的AMPK。我们试图研究普伐他汀对AAA形成的影响，并揭示其分子机制。由AngII诱导AAA模型，并通过Apoe−/−小鼠的发病率、弹性蛋白降解和最大腹主动脉直径进行评价。在培养的血管平滑肌细胞（VSMC）或小鼠中检测AMPKa 2和激活蛋白2 α（AP-2a）的磷酸化水平。我们观察到普伐他汀（50 mg/kg/天，8周）显著增加了小鼠血管紧张素II诱导的AAA发病率。在VSMC中，普伐他汀在基础和AngII应激条件下均增加pAMPK、pAP-2a和MMP 2的水平，tempol和化合物C可消除这些作用。AMPKa 2或AP-2a siRNA可阻断普伐他汀上调的MMP 2表达。慢病毒介导的AMPKa 2或AP-2a基因沉默消除了AngII输注Apoe−/−小鼠中普伐他汀恶化的AAA形成。临床研究表明，服用普伐他汀的AAA患者或人类受试者中AMPKa 2和AP-2a磷酸化均增加。总之，普伐他汀通过AMPKa 2依赖性AP-2a激活促进AAA形成。
We have previously reported that activation of AMP-activated kinase alpha 2 (AMPKa2) by nicotine or angiotensin II (AngII) instigates formation of abdominal aortic aneurysms (AAA) in Apoe−/− mice. Statins, used to treat hyperlipidemia widely, activate AMPK in vascular cells. We sought to examine the effects of pravastatin on AAA formation and uncover the molecular mechanism. The AAA model was induced by AngII and evaluated by incidence, elastin degradation, and maximal abdominal aortic diameter in Apoe−/− mice. The phosphorylated levels of AMPKa2 and activator protein 2 alpha (AP-2a) were examined in cultured vascular smooth muscle cells (VSMCs) or in mice. We observed that pravastatin (50 mg/kg/day, 8 weeks) remarkably increased the AngII-induced AAA incidence in mice. In VSMCs, pravastatin increased the levels of pAMPK, pAP-2a, and MMP2 in both basal and AngII-stressed conditions, which were abolished by tempol and compound C. Pravastatin-upregulated MMP2 was abrogated by AMPKa2 or AP-2a siRNA. Lentivirus-mediated gene silence of AMPKa2 or AP-2a abolished pravastatin-worsened AAA formations in AngII-infused Apoe−/− mice. Clinical investigations demonstrated that both AMPKa2 and AP-2a phosphorylations were increased in AAA patients or human subjects taking pravastatin. In conclusion, pravastatin promotes AAA formation through AMPKa2-dependent AP-2a activations.