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.
Yubo TangQingde WaLong-Yun PengYifan ZhengJie ChenXiao ChenXuenong ZouHuangxuan ShenShuai HuangPublished in: Oxidative medicine and cellular longevity (2022)
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-) 1 β 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.
Keyphrases
- nlrp inflammasome
- cell death
- stress induced
- endoplasmic reticulum
- signaling pathway
- reactive oxygen species
- pi k akt
- transcription factor
- oxidative stress
- endothelial cells
- anti inflammatory
- cell migration
- cell cycle arrest
- skeletal muscle
- induced apoptosis
- dna binding
- epithelial mesenchymal transition
- single cell
- protein kinase
- poor prognosis
- cardiovascular disease
- endoplasmic reticulum stress
- cell proliferation
- mesenchymal stem cells
- diffuse large b cell lymphoma
- estrogen receptor
- cell therapy
- genome wide
- gene expression
- breast cancer cells
- human health
- pulmonary hypertension
- dna damage
- binding protein
- risk assessment
- bone marrow
- cancer therapy
- drug delivery
- induced pluripotent stem cells