P2Y(2)R activation by ATP induces oxLDL-mediated inflammasome activation through modulation of mitochondrial damage in human endothelial cells

초록

Oxidative stress and the related inflammatory responses are closely associated with many diseases including cardiovascular diseases such as atherosclerosis. Especially, mitochondrial damage and inflammasome activation have been reported to be directly involved in atherogenesis. In addition, we previously reported that endothelial cells (ECs) exposed to oxidized LDL (oxLDL) release ATP, which activates P2Y(2)R, resulting in the expression of receptors for advanced glycation end products and adhesion molecules that are involved in the pathogenesis of atherosclerosis. Therefore, it is expected that P2Y(2)R activation by ATP released under inflammatory conditions may be linked to the inflammasome-mediated pathogenesis of cardiovascular diseases such as atherosclerosis. However, the exact association remains unclear. Thus, in this study, we investigated the role of P2Y(2)R in oxLDL-mediated inflammasome activation and the related atherosclerotic pathogenesis in ECs. ECs stimulated with oxLDL demonstrated increased intracellular production and extracellular secretion of ATP. In addition, mitochondrial reactive oxygen species (mtROS) production and mitochondrial DNA (mtDNA) expression and cytosolic release were increased in ECs stimulated with oxLDL or the P2Y(2)R agonists ATP and UTP. Moreover, caspase-1 activity and IL-1 beta production were increased in ECs stimulated with oxLDL, ATP or UTP through the modulation of mtROS production and mtDNA expression, in a P2Y(2)R-dependent manner. Furthermore, TLR-9 and NF-kappa B activation was increased in ECs in response to oxLDL, ATP or UTP, in a mtDNA-dependent manner. Taken together, our findings suggest that P2Y(2)R activation by ATP is involved in oxLDL-mediated inflammasome activation and subsequent IL-1 beta production through the modulation of mtROS-mtDNA induction and the TLR9-NF-kappa B signaling pathway.

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