LncRNA GAS5 downregulates NLRP3 inflammasome activation-mediated pyroptosis in sepsis-induced myocardial injury by targeting SIRT3/AMPKα

Minghao Luo; Yuce Peng; Dingyi Lv; Yuzhou Xue; Longxiang Huang; Yu Hu; Wenyan Zhu; Suxin Luo; Jian Shen; Xiang Li

doi:10.1016/j.heliyon.2023.e22939

LncRNA GAS5 downregulates NLRP3 inflammasome activation-mediated pyroptosis in sepsis-induced myocardial injury by targeting SIRT3/AMPKα

Heliyon. 2023 Nov 28;9(12):e22939. doi: 10.1016/j.heliyon.2023.e22939. eCollection 2023 Dec.

Authors

Minghao Luo^{1

2}, Yuce Peng^{1

2}, Dingyi Lv^{1

2}, Yuzhou Xue¹, Longxiang Huang¹, Yu Hu^{1

2}, Wenyan Zhu³, Suxin Luo^{1

4}, Jian Shen¹, Xiang Li¹

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
² Cardiovascular Disease Laboratory of Chongqing Medical University, 400016, Chongqing, China.
³ Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing, 401331, China.
⁴ Medical Data Research Institute of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China.

Abstract

An increasing body of studies has demonstrated the significance of long non-coding RNA (lncRNA) growth arrest specific 5 (GAS5) in inflammation and myocardial injury in septic shock. This research aims to determine whether GAS5 contributes to the pathological development of sepsis-induced cardiac damage and NLRP3 inflammasome-mediated myocardial cell pyroptosis. Cecal ligation and puncture (CLP) surgery was used to cause septic shock in C57BL/6 wild-type mice. After CLP, inflammatory, pyroptosis parameters of myocardial tissue, survival rate, and Murine Sepsis Score (MSS) were assessed to evaluate the involvement of GAS5 in the mouse myocardial depression. To investigate GAS5's function in lipopolysaccharide (LPS) induced myocardial cell pyroptosis, gain- and loss-of-function experiments were conducted in vitro on HL-1 cells. Our findings indicated that CLP dramatically reduced survival rates, MSS, SIRT3 and p-AMPK expression, and activated the Nuclear factor-κB (NF-κB) pathway and NLRP3 inflammasome-mediated pyroptosis. The NF-κB and pyroptosis pathways were greatly elevated while SIRT3/p-AMPKα was dramatically decreased as a result of GAS5 being downregulated. Meanwhile, the regulatory effect could be suppressed by SIRT3 and AMPKα activator. Our observations supported the idea that GAS5 has a crucial protective impact against myocardial inflammation and pyroptosis in sepsis.

Keywords: GAS5; Myocardial injury; Pyroptosis; Sepsis.