Zou Sili, Ren Pingping, Zhang Lin, Azares Alon R, Zhang Sui, Coselli Joseph S, Shen Ying H, LeMaire Scott A
Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, Texas; Department of Vascular Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, Texas.
Ann Thorac Surg. 2016 Jun;101(6):2085-96. doi: 10.1016/j.athoracsur.2016.01.026. Epub 2016 Apr 16.
Insufficient aortic protection and repair may contribute to the development of aortic aneurysms and dissections (AAD). However, mechanisms of aortic protection and repair are poorly understood. We have shown that the multifunctional kinase AKT2 plays an important role in protecting the aortic wall. Here, we examined whether AKT2 protects against AAD by promoting bone marrow cell (BMC)-mediated aortic protection.
Irradiated wild-type mice received green fluorescent protein-expressing BMCs from wild-type mice or Akt2(-/-) mice, followed by challenge with angiotensin II (1000 ng/kg/min) infusion for 4 weeks. We compared BMC recruitment, aortic destruction, and AAD development between groups. The direct effects of wild-type and Akt2(-/-) BMCs on smooth muscle cell survival were examined in coculture experiments.
After angiotensin II infusion, no (0 of 14) wild-type BMC recipients had AAD; in contrast, 64% (9 of 14) of Akt2(-/-) BMC recipients had AAD (p = 0.002) with severe aortic destruction. Compared with aortas from challenged wild-type BMC recipients, aortas from challenged Akt2(-/-) BMC recipients showed significantly less BMC recruitment, NG2 (neuron-glial antigen 2) progenitor activation, and FSP1 (fibroblast-specific protein 1) fibroblast activation. In addition, aortas from challenged Akt2(-/-) BMC recipients showed increased apoptosis and inflammation. In coculture experiments, wild-type but not Akt2(-/-) BMCs prevented smooth muscle cells from undergoing oxidative stress-induced apoptosis.
After aortic challenge, BMCs are recruited to the aortic wall and provide protection by activating progenitors and fibroblasts and by promoting aortic cell survival. Our findings indicate that AKT2 is involved in these processes and that defects in this pathway may promote progressive degeneration during AAD development.
主动脉保护和修复不足可能导致主动脉瘤和主动脉夹层（AAD）的发生。然而，主动脉保护和修复的机制尚不清楚。我们已经表明多功能激酶AKT2在保护主动脉壁中起重要作用。在此，我们研究了AKT2是否通过促进骨髓细胞（BMC）介导的主动脉保护来预防AAD。
经照射的野生型小鼠接受来自野生型小鼠或Akt2基因敲除小鼠的表达绿色荧光蛋白的BMC，随后用血管紧张素II（1000 ng/kg/分钟）输注进行4周的刺激。我们比较了各组之间的BMC募集、主动脉破坏和AAD发生情况。在共培养实验中检测了野生型和Akt2基因敲除BMC对平滑肌细胞存活的直接影响。
血管紧张素II输注后，野生型BMC受体中无一例（0/14）发生AAD；相比之下，Akt2基因敲除BMC受体中有64%（9/14）发生AAD（p = 0.002），伴有严重的主动脉破坏。与接受刺激的野生型BMC受体的主动脉相比，接受刺激的Akt2基因敲除BMC受体的主动脉显示出明显更少的BMC募集、NG2（神经胶质抗原2）祖细胞激活和FSP1（成纤维细胞特异性蛋白1）成纤维细胞激活。此外，接受刺激的Akt2基因敲除BMC受体的主动脉显示凋亡和炎症增加。在共培养实验中，野生型而非Akt2基因敲除的BMC可防止平滑肌细胞发生氧化应激诱导的凋亡。
主动脉受到刺激后，BMC被募集到主动脉壁，并通过激活祖细胞和成纤维细胞以及促进主动脉细胞存活来提供保护。我们的研究结果表明AKT2参与了这些过程，并且该途径中的缺陷可能在AAD发展过程中促进进行性退变。
