c-Abl调控的信号通路在主动脉夹层发病机制中的作用

The pathogenesis of aortic dissection remains unclear. It was confirmed that vascular smooth muscle cells（VSMCs） can maintain the stability of the aortic wall, apoptosis and phenotypic transformation of VSMCs play an important role in pathogenesis of aortic dissection. Abelson tyrosine kinase (c-Abl) is involved in regulation of many signal pathway, including cytoskeleton,apoptosis, and phenotypic transformation. Our privious study found that (1) Arterial blood pressure in Abl knockout mice was lower than that in wild type mice, the undrerlying mechanism was that the tone of blood vessel was regulated by reducing the phosphorylation of CAS protein and expression of focal adhesion associated proteins; (2) The expression of c-Abl and apoptosis related proteins increased in the sample of patients with aortic dissection；（3）AngⅡ-induced VSMC apoptosis and aortic dissection can be restrained by c-Abl inhibitor STI571. This study is to observe effect of c-Abl activation on VSMCs apoptosis and phenotypic transformation, and modulation of JAK/STAT，JNK and p8MAPK signal pathway by over-expression, gene silencing and inhibitor of c-Abl in vitro; and to investigate molecular mechanism of c-Abl involved in pathogenesis of aortic dissection with Abl-/- mice in vivo, providing a new strategy for prevention and treatment of aortic dissection.

主动脉夹层发病机制仍不清楚。已证实，血管平滑肌细胞(VSMC)可维持主动脉壁稳定性，VSMC凋亡和表型转化在主动脉夹层发病机制中具有重要作用。c-Abl调控多条信号通路转导，包括细胞骨架、凋亡、表型转化等。我们前期研究发现：（1）Abl基因敲除小鼠的尾动脉血压低于同种系野生型小鼠，其机制是通过减少CAS蛋白磷酸化和黏着斑相关支架蛋白的表达，调节血管平滑肌张力；（2）夹层患者的主动脉标本中c-Abl和凋亡相关蛋白表达均增加；（3）c-Abl抑制剂STI571可抑制Ang Ⅱ诱导的VSMC凋亡，并减少小鼠主动脉夹层发生率。本课题拟通过c-Abl过表达、基因沉默或活性抑制,观察其对VSMC凋亡和表型转化的影响，以及对JAK/STAT、JNK和p38MAPK信号通路的调控作用。利用Abl-/-小鼠，深入探讨 c-Abl参与夹层发病的主要分子机制，为防治主动脉夹层提供理论依据和新的干预靶点。

血管紧张素II（Ang II）可通过调节血管平滑肌细胞（VSMCs）的病理变化诱导主动脉夹层（AD）发生。 然而，这一过程所涉及的分子机制还不完全清楚。 本研究的目的是研究原癌基因非受体细胞Abelson酪氨酸激酶（c-Abl）在Ang II诱导的VSMCs表型转化和凋亡中的潜在作用。通过体外实验比较c-Abl过表达、基因沉默或活性抑制对VSMCs凋亡和表型转化的影响，研究c-Abl对JAK/STAT、JNK和p38MAPK信号通路的调控作用。利用Abl-/+小鼠，在Ang Ⅱ诱导的主动脉夹层动物模型上，验证 c-Abl参与夹层发病的主要分子机制。结果发现，Ang II输注诱导野生型C57小鼠AD发生（27％; 8/30），而STI571灌胃或Abl1基因敲除使小鼠AD发生率分别降低至13％（4/30）和7％（2/30） 并伴随着降主动脉最大直径的减小。体内和体外的研究结果表明，c-Abl过表达可增强AngII诱导的VSMCs凋亡和合成表型转化，而Abl1基因敲除或STI571抑制c-Abl活性则显着减弱上述病理改变。并且AngII诱导VSMCs凋亡和表型转变是通过JAK/STAT、JUK和p38MAPK三条信号通路介导的。本项目初步明确了c-Abl参与主动脉夹层发病的分子机制，为将来防治主动脉夹层提供了理论基础及实验依据。