Cyclooxygenase-2 inhibition attenuates abdominal aortic aneurysm progression in hyperlipidemic mice.
Cyclooxygenase-2 inhibition attenuates abdominal aortic aneurysm progression in hyperlipidemic mice.
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DOI：
10.1371/journal.pone.0044369
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Loftin CD
中科院分区：
文献类型：
--
作者：
Ghoshal S;Loftin CD
腹主动脉瘤（AAAs）是一种慢性炎症性疾病，可增加危及生命的主动脉破裂风险。在人类中，AAA的特征是环氧化酶-2的表达增加，在疾病开始前COX-2的失活降低了AAA在疾病小鼠模型中的发病率。目前的研究检验了选择性环氧合酶-2 （COX-2）抑制在AAA形成开始后对降低AAA进展的有效性。通过慢性血管紧张素II （AngII）输注诱导高脂血症载脂蛋白e缺乏小鼠的AAAs，并在疾病的不同阶段开始时，观察COX-2抑制剂塞来昔布治疗的效果。在开始AngII输注1周后开始塞来昔布治疗，可使AAA发生率降低61%，并显著降低AAA严重程度。用塞来昔布治疗的小鼠也显示出主动脉破裂和死亡率的显著降低。在AAA发展晚期开始使用塞来昔布治疗也可显著降低AAA发生率和严重程度。塞来昔布治疗显著增加腹主动脉平滑肌α -肌动蛋白的表达，并没有降低巨噬细胞依赖性炎症标志物的表达。这些发现表明，在血管诱导的AAAs形成后开始的COX-2抑制剂治疗有效地减少了高脂血症小鼠的疾病进展。
Abdominal aortic aneurysms (AAAs) are a chronic inflammatory disease that increase the risk of life-threatening aortic rupture. In humans, AAAs have been characterized by increased expression of cyclooxygenase-2 and the inactivation of COX-2 prior to disease initiation reduces AAA incidence in a mouse model of the disease. The current study examined the effectiveness of selective cyclooxygenase-2 (COX-2) inhibition on reducing AAA progression when administered after the initiation of AAA formation. AAAs were induced in hyperlipidemic apolipoprotein E-deficient mice by chronic angiotensin II (AngII) infusion and the effect of treatment with the COX-2 inhibitor celecoxib was examined when initiated at different stages of the disease. Celecoxib treatment that was started 1 week after initiating AngII infusion reduced AAA incidence by 61% and significantly decreased AAA severity. Mice treated with celecoxib also showed significantly reduced aortic rupture and mortality. Treatment with celecoxib that was started at a late stage of AAA development also significantly reduced AAA incidence and severity. Celecoxib treatment significantly increased smooth muscle alpha-actin expression in the abdominal aorta and did not reduce expression of markers of macrophage-dependent inflammation. These findings indicate that COX-2 inhibitor treatment initiated after formation of AngII-induced AAAs effectively reduces progression of the disease in hyperlipidemic mice.
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