Salvianolic Acid B Suppresses ER Stress-Induced NLRP3 Inflammasome and Pyroptosis via the AMPK/FoxO4 and Syndecan-4/Rac1 Signaling Pathways in Human Endothelial Progenitor Cells

Author:

Tang Yubo1ORCID,Wa Qingde2ORCID,Peng Longyun3ORCID,Zheng Yifan1ORCID,Chen Jie1ORCID,Chen Xiao1ORCID,Zou Xuenong4ORCID,Shen Huangxuan5ORCID,Huang Shuai6ORCID

Affiliation:

1. Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China

2. Department of Orthopaedic Surgery, The Second Affiliated Hospital of Zunyi Medical University, 563000 Zunyi, China

3. Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China

4. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China

5. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

6. Department of Orthopaedic Surgery, The Second Affiliated Hospital, Guangzhou Medical University, 510260 Guangzhou, China

Abstract

Mounting evidence demonstrates uncontrolled endoplasmic reticulum (ER) stress responses can activate the inflammasome, which generally results in endothelial dysfunction, a major pathogenetic factor of chronic inflammatory diseases such as atherosclerosis. Salvianolic acid B (SalB), produced by Radix Salviae, exerts antioxidative and anti-inflammatory activities in multiple cell types. However, SalB’s effects on ER stress-related inflammasome and endothelial dysfunction remain unknown. Here, we showed SalB substantially abrogated ER stress-induced cell death and reduction in capillary tube formation, with declined intracellular reactive oxygen species (ROS) amounts and restored mitochondrial membrane potential (MMP), as well as increased expression of HO-1 and SOD2 in bone marrow-derived endothelial progenitor cells (BM-EPCs). ER stress suppression by CHOP or caspase-4 siRNA transfection attenuated the protective effect of SalB. Additionally, SalB alleviated ER stress-mediated pyroptotic cell death via the suppression of TXNIP/NLRP3 inflammasome, as evidenced by reduced cleavage of caspase-1 and interleukin- (IL-) 1β and IL-18 secretion levels. Furthermore, this study provided a mechanistic basis that AMPK/FoxO4/KLF2 and Syndecan-4/Rac1/ATF2 signaling pathway modulation by SalB substantially prevented BM-EPCs damage associated with ER stress by decreasing intracellular ROS amounts and inducing NLRP3-dependent pyroptosis. In summary, our findings identify that ER stress triggered mitochondrial ROS release and NLRP3 generation in BM-EPCs, while SalB inhibits NLRP3 inflammasome-mediated pyroptotic cell death by regulating the AMPK/FoxO4/KLF2 and Syndecan-4/Rac1/ATF2 pathways. The current findings reveal SalB as a potential new candidate for the treatment of atherosclerotic heart disease.

Funder

Fundamental Research Funds for the Central Universities

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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