scholarly journals P2X7 Receptor Antagonist Attenuates Retinal Inflammation and Neovascularization Induced by Oxidized Low-Density Lipoprotein

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Mingzhu Yang ◽  
Ruiqi Qiu ◽  
Weiping Wang ◽  
Jingyang Liu ◽  
Xiuxiu Jin ◽  
...  

Age-related macular degeneration (AMD) is a common and severe blinding disease among people worldwide. Retinal inflammation and neovascularization are two fundamental pathological processes in AMD. Recent studies showed that P2X7 receptor was closely involved in the inflammatory response. Here, we aim to investigate whether A740003, a P2X7 receptor antagonist, could prevent retinal inflammation and neovascularization induced by oxidized low-density lipoprotein (ox-LDL) and explore the underlying mechanisms. ARPE-19 cells and C57BL/6 mice were treated with ox-LDL and A740003 successively for in vitro and in vivo studies. In this research, we found that A740003 suppressed reactive oxygen species (ROS) generation and inhibited the activation of Nod-like receptor pyrin-domain protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathway. A740003 also inhibited the generation of angiogenic factors in ARPE-19 cells and angiogenesis in mice. The inflammatory cytokines and phosphorylation of inhibitor of nuclear factor-κB alpha (IKBα) were repressed by A740003. Besides, ERG assessment showed that retinal functions were remarkably preserved in A740003-treated mice. In summary, our results revealed that the P2X7 receptor antagonist reduced retinal inflammation and neovascularization and protected retinal function. The protective effects were associated with regulation of NLRP3 inflammasome and the NF-κB pathway, as well as inhibition of angiogenic factors.

1997 ◽  
Vol 17 (10) ◽  
pp. 1901-1909 ◽  
Author(s):  
Korbinian Brand ◽  
Tamara Eisele ◽  
Ursula Kreusel ◽  
Michael Page ◽  
Sharon Page ◽  
...  

2000 ◽  
Vol 350 (3) ◽  
pp. 829-837 ◽  
Author(s):  
Chang-Yeop HAN ◽  
Soo-Young PARK ◽  
Youngmi Kim PAK

Oxidized low-density lipoprotein (oxLDL) has been shown to modulate transactivation by the peroxisome proliferator-activated receptor (PPAR)-γ and by nuclear factor-κB (NF-κB). In the present study, the oxLDL signalling pathways involved in NF-κB transactivation were investigated by utilizing a reporter construct driven by three upstream NF-κB binding sites, and various pharmacological inhibitors. OxLDL and its constituent lysophophatidylcholine (lysoPC) induced a rapid and transient increase in intracellular calcium and stimulated NF-κB transactivation in resting RAW264.7 macrophage cells in an oxidation-dependent manner. NF-κB activation by oxLDL or lysoPC was inhibited by inhibitors of protein kinase C or by a chelator of intracellular calcium. Tyrosine kinase or phosphatidylinositol 3-kinase inhibitors did not block NF-κB transactivation. Furthermore, oxLDL-induced NF-κB activity was abolished by PPAR-γ ligands. When the endocytosis of oxLDL was blocked by cytochalasin B, NF-κB transactivation by oxLDL was synergistically increased, while PPAR transactivation was blocked. These results suggest that oxLDL activates NF-κB in resting macrophages via protein kinase C- and/or calcium-dependent pathways, and that this does not involve the endocytic processing of oxLDL. The endocytosis-dependent activation of PPAR-γ by oxLDL may function as a route of inactivation of the oxLDL-induced NF-κB signal.


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