AKT2 confers protection against aortic aneurysms and dissections.
AKT2 confers protection against aortic aneurysms and dissections.
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DOI：
10.1161/circresaha.112.300735
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发表时间：
2013-02-15
影响因子：
20.1
通讯作者：
LeMaire SA
中科院分区：
文献类型：
--
作者：
Shen YH;Zhang L;Ren P;Nguyen MT;Zou S;Wu D;Wang XL;Coselli JS;LeMaire SA
主动脉瘤及夹层（AAD）是由主动脉壁进行性内侧退变引起的成人主动脉主要疾病。虽然破坏性因子的过量产生促进组织损伤和疾病进展，但保护性途径的作用尚不清楚。在这项研究中，我们研究了AKT2在保护主动脉不发生AAD中的作用。AKT2和磷酸化akt水平在人胸椎AAD组织中显著下调，尤其是在退行性内侧层。akt2缺陷小鼠显示弹性纤维异常，主动脉壁内侧厚度减少。当使用血管紧张素II （AngII）时，这些小鼠在胸腹段出现了与人类相似的主动脉瘤、夹层和破裂。akt2缺陷小鼠的主动脉表现出严重的组织破坏、细胞凋亡和炎症细胞浸润，而这些在野生型小鼠的主动脉中没有观察到。此外，血管注入akt2缺陷小鼠的基质金属蛋白酶(MMP)-9的表达显著升高，金属蛋白酶组织抑制剂(TIMP)-1的表达显著降低。在培养的人主动脉血管平滑肌细胞中，AKT2通过阻止转录因子叉头盒蛋白O1 （FOXO1）与MMP-9和TIMP-1启动子的结合，抑制MMP-9的表达，刺激TIMP-1的表达。受损的AKT2信号可能会增加对AAD发展的易感性。我们的研究结果为AKT2对主动脉壁保护作用的机制提供了证据，并可能作为预防AAD的治疗靶点。
Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown. In this study, we examined the role of AKT2 in protecting the aorta from developing AAD. AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2-deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II (AngII), these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2-deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. Additionally, AngII-infused Akt2-deficient mice showed significantly elevated expression of matrix metalloproteinase (MMP)-9 and reduced expression of tissue inhibitor of metalloproteinase (TIMP)-1. In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 (FOXO1) to the MMP-9 and TIMP-1 promoters. Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.