Through RAGE-dependent PERK/eIF2alpha pathway, HMGB1 can induces endothelial progenitor cells apoptosis

HMGB1 molecular pathway

HMGB1 research brief

The function of high-mobility group 1B protein (HMGB1) for regulating endothelial progenitor cell (EPC) homing had been discovered in several studies.However, the mechanism of HMGB1 for EPC apoptosis still remained unclear. This study was designed to investigate the effects of HMGB1 on EPC apoptosis and the possible involvement of the endoplasmic reticulum (ER) stress pathway. EPC apoptosis and expression of PERK, eIF2alpha, and CHOP was determined by flow cytometry and  western blotting, seperately. In additon, the effects of PERK shRNA on the biological behaviors of EPCs were also determined. The results of this study revealed that incubation of EPCs with HMGB1 for 12–48 h could induce apoptosis and activated ER stress transducers as well. This was determined by up-regulating PERK protein expression and eIF2alpha phosphorylation in a dose or time-dependent manner. Importantly, HMGB1-mediated EPC apoptosis and CHOP expression were dramatically suppressed by PERK shRNA or a specific eIF2alpha inhibitor. Finally, an antibody targeting against RAGE (anti-RAGE antibody) with blockage, could markedly inhibit HMGB1-induced EPC apoptosis and PERK, eIF2-alpha, and CHOP expressions. This study suggests that HMGB1 triggered EPC apoptosis in a manner of RAGE-mediated activation of the PERK/eIF2alpha pathway.

Endothelial progenitor cells (EPCs) play critical roles in various human diseases such as atherosclerosis and vascular repair at sites of ischaemia (myocardial infarction, peripheral artery disease, and stroke). EPC dysfunction is proved to be associated with thrombotic complication, atherosclerosis, and other cardiovascular diseases . A reduced number of EPC is an independent predictor of morbidity and mortality of cardiovascular diseases. Risk factors of atherosclerosis, such as diabetes, aging, hypercholesterolemia, hypertension and smoking, could impair the function of EPCs partly via promoting EPC apoptosis. However, the underlying mechanism of EPC apoptosis remains unclear. High-mobility group 1B protein (HMGB1), a 30  kDa nuclear protein, can be released by inflammatory cells or necrotic cells to trigger inflammation, which plays an important role in regulating development of atherosclerosis. Recent studies have indicated that HMGB1 can alter EPC functions and survival. Such as, HMGB1 attracts endothelial progenitor cells and hematopoietic stem cells to the sites of tissue injury and tumors in order to promote neovascularization.More recently, Hayakawa et  al. reported that astrocytic HMGB1 promoted endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Besides, HMGB1 also inhibits the proliferation of human mesenchymal stem cells and promotes their migration and differentiation along osteoblastic pathway. However, the effect of HMGB1 on EPC apoptosis and associated mechanisms are still unclear.

HMGB1 Research highlight

  • HMGB1 induces apoptosis and activated PERK/ eIF2alpha pathway in EPCs
  • EPC was characterized using cytometry
  • HMGB1 triggered PERK/ eIF2alpha pathway to activate CHOP-dependent apoptosis pathways and subsequently caused EPC apoptosis

 

HMGB1 Research conclusion

In conclusion, the present study indicates that HMGB1 triggers apoptosis of EPCs by inducing the expression of CHOP via RAGE-mediated stimulation of PERK/ eIF2alpha stress pathway. These findings may explain the important mechanism through which HMGB1 causes EPC dysfunction and provide an alternative target for drug development and clinical treatment for vascular diseases.

Original paper: https://link.springer.com/article/10.1007%2Fs11010-017-2976-2

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