Stress granule activation attenuates lipopolysaccharide-induced cardiomyocyte dysfunction

BMC Cardiovascular Disorders

Research

Yusheng Wang¹  Gaowei Yang¹  Runmin Liu¹  Hao Wang¹  Yaqiao Wang¹  Kehan Wu¹  Tao Rui¹ 

[1] Division of Cardiology, Department of Medicine, the Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China;

关键词: Stress granule;    Sepsis;    Myocardial dysfunction;    G3BP1;    Mitochondria;   

DOI  :  10.1186/s12872-023-03281-0

 received in 2023-02-21, accepted in 2023-05-07,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSepsis is the leading cause of death in intensive care units. Sepsis-induced myocardial dysfunction, one of the most serious complications of sepsis, is associated with higher mortality rates. As the pathogenesis of sepsis-induced cardiomyopathy has not been fully elucidated, there is no specific therapeutic approach. Stress granules (SG) are cytoplasmic membrane-less compartments that form in response to cellular stress and play important roles in various cell signaling pathways. The role of SG in sepsis-induced myocardial dysfunction has not been determined. Therefore, this study aimed to determine the effects of SG activation in septic cardiomyocytes (CMs).MethodsNeonatal CMs were treated with lipopolysaccharide (LPS). SG activation was visualized by immunofluorescence staining to detect the co-localization of GTPase-activating protein SH3 domain binding protein 1 (G3BP1) and T cell-restricted intracellular antigen 1 (TIA-1). Eukaryotic translation initiation factor alpha (eIF2α) phosphorylation, an indicator of SG formation, was assessed by western blotting. Tumor necrosis factor alpha (TNF-α) production was assessed by PCR and enzyme-linked immunosorbent assays. CMs function was evaluated by intracellular cyclic adenosine monophosphate (cAMP) levels in response to dobutamine. Pharmacological inhibition (ISRIB), a G3BP1 CRISPR activation plasmid, and a G3BP1 KO plasmid were employed to modulate SG activation. The fluorescence intensity of JC-1 was used to evaluate mitochondrial membrane potential.ResultsLPS challenge in CMs induced SG activation and resulted in eIF2α phosphorylation, increased TNF-α production, and decreased intracellular cAMP in response to dobutamine. The pharmacological inhibition of SG (ISRIB) increased TNF-α expression and decreased intracellular cAMP levels in CMs treated with LPS. The overexpression of G3BP1 increased SG activation, attenuated the LPS-induced increase in TNF-α expression, and improved CMs contractility (as evidenced by increased intracellular cAMP). Furthermore, SG prevented LPS-induced mitochondrial membrane potential dissipation in CMs.ConclusionSG formation plays a protective role in CMs function in sepsis and is a candidate therapeutic target.

【 授权许可】

CC BY   
© The Author(s) 2023

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