Role of c-Abl in Ang II-induced aortic dissection formation: Potential regulatory efficacy on phenotypic transformation and apoptosis of VSMCs
2020
Zhou, Xianwu | Cheng, Jiancheng | Chen, Zerui | Li, Huadong | Chen, Shu | Xu, Fei | Fan, Ruixin | Zhuang, Jian | Sun, Tucheng
Angiotensin II (Ang II) induces aortic dissection (AD) via regulation of pathological changes in vascular smooth muscle cells (VSMCs). However, the molecular mechanisms involved are not fully understood. The aim of this study was to evaluate the potential role of the proto-oncogene non-receptor cellular Abelson tyrosine kinase (c-Abl) in Ang II-induced VSMC phenotypic transformation and apoptosis.Lentiviral transfection and short hairpin RNA (shRNA) were used to enhance or inhibit c-Abl in cultured VSMCs. In addition, C57BL/6 and Abl1 gene knockout heterozygous (c-Abl⁻/⁺) mice were infused with Ang II, with or without c-Abl inhibitor (STI571) treatment. The incidence of AD was evaluated in vivo, while the molecular and pathological features of VSMC phenotypic transformation and apoptosis were evaluated in vitro and in vivo.Ang II infusion induced a substantial incidence of AD in vivo (27%; 8/30), while STI571 intragastric gavage or Abl1 knockout reduced the incidence of AD to 13% (4/30) and 7% (2/30), respectively. The results of subsequent studies showed that c-Abl overexpression enhanced the Ang II-induced apoptosis and synthetic phenotypic transformation of VSMCs in vitro, while inhibition of c-Abl activity with STI571 or Abl1 gene knockout significantly attenuated the Ang II-induced apoptosis and synthetic phenotypic transformation of VSMCs both in vivo and in vitro.Activation of c-Abl may be important for the phenotypic transformation and apoptosis of VSMCs underlying the Ang II-induced AD. Targeted inhibition of c-Abl may prevent Ang II-induced AD via attenuation of the pathological changes of VSMCs.
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