Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, 238# Jiefang Road, Wuhan 430000, Hubei Province, People's Republic of China; Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, 9# Zhangzhidong Road, Wuhan 430000, Hubei Province, People's Republic of China; Central Laboratory, Renmin Hospital of Wuhan University, 9# Zhangzhidong Road, Wuhan 430000, Hubei Province, People's Republic of China.
Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, 238# Jiefang Road, Wuhan 430000, Hubei Province, People's Republic of China; Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, 9# Zhangzhidong Road, Wuhan 430000, Hubei Province, People's Republic of China.
Life Sci. 2019 May 1;224:51-57. doi: 10.1016/j.lfs.2019.03.052. Epub 2019 Mar 21.
The pathogenesis of abdominal aortic aneurysm remains unclear. The aim of the present study was to establish whether isoleucyl-tRNA synthetase (Iars) regulates the differentiation and apoptosis of vascular smooth muscle cells (VSMCs) during the development of abdominal aortic aneurysm (AAA). In addition, the contribution of various signaling pathways towards this process was ascertained. The study demonstrated that the expression of Iars, p-p38, osteopontin (OPN) and Bcl-2-associated X protein (Bax) clearly increased, while levels of p-PI3K and smooth muscle 22 alpha (SM22α) decreased significantly in AAA tissues. Inhibition of Iars significantly reduced the incidence of angiotensin II (AngII)-induced AAA in mice, coincident with decreased activity of the p38 MAPK pathway and increased PI3K pathway activity. AngII-induced phenotypic switching and apoptosis of VSMCs decreased following the inhibition of Iars in vitro. Upregulation of the IARS gene induced phenotypic switching and apoptosis in VSMCs in addition to increased p38 MAPK pathway activation and reduced PI3K pathway activation. Following pretreatment with an activator of the PI3K pathway, expression of Iars and the phenotypic markers of VSMCs were not affected, while apoptosis of VSMCs decreased. Similarly, inhibition of the p38 MAPK pathway in VSMCs did not affect the expression of Iars or the degree of cell apoptosis, but reduced phenotypic switching was observed. Conclusively, upregulation of Iars regulates the phenotypic switching and apoptosis of VSMCs. Targeting Iars may be a promising strategy to prevent abdominal aortic aneurysm.
腹主动脉瘤的发病机制尚不清楚。本研究旨在确定异亮氨酰-tRNA 合成酶（Iars）是否在腹主动脉瘤（AAA）的发展过程中调节血管平滑肌细胞（VSMCs）的分化和凋亡。此外，还确定了各种信号通路对这一过程的贡献。研究表明，Iars、p-p38、骨桥蛋白（OPN）和 Bcl-2 相关 X 蛋白（Bax）的表达明显增加，而 AAA 组织中 p-PI3K 和平滑肌 22α（SM22α）的水平显著降低。Iars 的抑制显著降低了 AngII 诱导的 AAA 在小鼠中的发生率，同时降低了 p38 MAPK 通路的活性和增加了 PI3K 通路的活性。体外抑制 Iars 可减少 AngII 诱导的 VSMCs 表型转换和凋亡。IARS 基因的上调除了激活 p38 MAPK 通路和减少 PI3K 通路的激活外，还诱导 VSMCs 的表型转换和凋亡。在用 PI3K 通路的激活剂预处理后，VSMCs 中 Iars 的表达和表型标志物不受影响，而 VSMCs 的凋亡减少。同样，VSMCs 中 p38 MAPK 通路的抑制不影响 Iars 的表达或细胞凋亡程度，但观察到表型转换减少。综上所述，Iars 的上调调节 VSMCs 的表型转换和凋亡。靶向 Iars 可能是预防腹主动脉瘤的一种有前途的策略。
