Xianwu Zhou1, Jiancheng Cheng2, Zerui Chen1, Huadong Li3, Shu Chen3, Fei Xu4, Ruixin Fan1, Jian Zhuang5, Tucheng Sun6. 1. Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangzhou 510100, PR China. 2. Cardiothoracic Surgery Department of Zhengzhou central hospital affiliated to Zhengzhou University, Zhengzhou, China. 3. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 4. Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan 430030, China. 5. Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangzhou 510100, PR China. Electronic address: zhuangjiangenetics@163.com. 6. Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangzhou 510100, PR China. Electronic address: suntucheng@126.com.
Abstract
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: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. SIGNIFICANCE: 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.