Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1764-71. doi: 10.1161/ATVBAHA.109.192609. Epub 2009 Sep 3.
Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over age 65. Generation of AAAs by infusion of angiotensin (Ang) II in apolipoprotein E-knockout (ApoE(-/-)) mice is an animal model which supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA. The effect of statins on AngII-mediated AAA formation and the associated neovascularization is not known. Here we determined the effect of simvastatin and the ERK inhibitor, CI1040, on AngII-stimulated AAA formation.
ApoE(-/-) mice infused for 28 days with AngII using osmotic minipumps were treated with placebo, 10 mg/kg/d simvastatin, or 100 mg/kg/d CI1040. 95% of AngII-treated mice developed AAA with neovascularization of the lesion, increased ERK phosphorylation, MCP-1 secretion, and MMP activity. These effects were markedly reversed by simvastatin and in part by CI1040. Furthermore, simvastatin and the ERK inhibitor U0126 reversed AngII-stimulated angiogenesis and MMP secretion by human umbilical vein endothelial cells.
These data support the conclusion that simvastatin interferes with AAA formation induced by AngII in ApoE(-/-) mice at least in part via ERK inhibition.
腹主动脉瘤（AAA）是一种危及生命的疾病，几乎影响了 10%以上的 65 岁以上人群。在载脂蛋白 E 基因敲除（ApoE(-/-)）小鼠中输注血管紧张素（Ang）II 生成 AAA 是一种动物模型，支持了肾素-血管紧张素系统在 AAA 发病机制中的失衡。他汀类药物对 AngII 介导的 AAA 形成和相关新生血管形成的影响尚不清楚。在此，我们确定了辛伐他汀和 ERK 抑制剂 CI1040 对 AngII 刺激的 AAA 形成的影响。
使用渗透微型泵对 ApoE(-/-) 小鼠输注 AngII 28 天，用安慰剂、10mg/kg/d 辛伐他汀或 100mg/kg/d CI1040 进行治疗。95%的 AngII 处理的小鼠发生 AAA，病变有新生血管形成，ERK 磷酸化、MCP-1 分泌和 MMP 活性增加。这些作用被辛伐他汀和部分 CI1040 明显逆转。此外，辛伐他汀和 ERK 抑制剂 U0126 逆转了 AngII 刺激的人脐静脉内皮细胞的血管生成和 MMP 分泌。
这些数据支持以下结论：辛伐他汀至少部分通过 ERK 抑制来干扰 AngII 在 ApoE(-/-) 小鼠中诱导的 AAA 形成。
