Theranostics 2019; 9(19):5558-5576. doi:10.7150/thno.34463

Research Paper

Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis

Xiang He1*, Shifei Wang1*, Mengsha Li1, Lintao Zhong1, Hao Zheng1, Yili Sun1, Yanxian Lai1, Xiaoqiang Chen1, Guoquan Wei1, Xiaoyun Si1, Yuan Han1, Senlin Huang1, Xinzhong Li1, Wangjun Liao2, Yulin Liao1, Jianping Bin1✉

1. Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
2. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
*These authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
He X, Wang S, Li M, Zhong L, Zheng H, Sun Y, Lai Y, Chen X, Wei G, Si X, Han Y, Huang S, Li X, Liao W, Liao Y, Bin J. Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis. Theranostics 2019; 9(19):5558-5576. doi:10.7150/thno.34463. Available from http://www.thno.org/v09p5558.htm

File import instruction

Abstract

Objective: Long noncoding RNAs (lncRNAs) may serve as specific targets for the treatment of abdominal aortic aneurysms (AAAs). LncRNA GAS5, functionally associated with smooth muscle cell (SMC) apoptosis and proliferation, is likely involved in AAA formation, but the exact role of GAS5 in AAA is unknown. We thus explored the contribution of GAS5 to SMC-regulated AAA formation and its underlying mechanisms.

Methods: Human specimens were used to verify the diverse expression of GAS5 in normal and AAA tissues. The angiotensin II (Ang II)-induced AAA model in ApoE-/- mice and the CaCl2-induced AAA model in wild-type C57BL/6 mice were used. RNA pull-down and luciferase reporter gene assays were performed in human aortic SMCs to detect the interaction between GAS5 and its downstream targets of protein or microRNA (miR).

Results: GAS5 expression was significantly upregulated in human AAA specimens and two murine AAA models compared to human normal aortas and murine sham-operated controls. GAS5 overexpression induced SMC apoptosis and repressed its proliferation, thereby promoting AAA formation in two murine AAA models. Y-box-binding protein 1 (YBX1) was identified as a direct target of GAS5 while it also formed a positive feedback loop with GAS5 to regulate the downstream target p21. Furthermore, GAS5 acted as a miR-21 sponge to release phosphatase and tensin homolog from repression, which blocked the activation and phosphorylation of Akt to inhibit proliferation and promote apoptosis in SMCs.

Conclusion: The LncRNA GAS5 contributes to SMC survival during AAA formation. Thus, GAS5 might serve as a novel target against AAA.

Keywords: GAS5, abdominal aortic aneurysm, Y-box-binding protein 1, microRNA-21, smooth muscle cell apoptosis