Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, 351 Tache Ave. Room R3022, Winnipeg, MB, R2H 2A6, Canada.
Department of Physiology and Pathophysiology, St. Boniface Hospital Albrechtsen Research Centre, 351 Tache Ave. Room R3022, Winnipeg, MB, R2H 2A6, Canada.
Sci Rep. 2020 Jul 21;10(1):12120. doi: 10.1038/s41598-020-68995-z.
Oxidized phospholipids (OxPLs) promote inflammation as well as low density lipoprotein (LDL) uptake in a variety of physiological and pathological states. Given the anti-inflammatory role of the cytokine IL-10, we investigated its modulatory effect on the production of oxidized phosphatidylcholines (OxPCs) as well as lipid metabolic responses in global myocardial ischemia/reperfusion (I/R) injury. Increased OxPCs levels, by 1-Palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (POVPC), promoted oxidative stress (OS) and cell death. OxPCs-mediated-OS, resulted in oxidized low-density lipoprotein receptor 1 (LOX-1) activation and upregulated the expression of toll-like receptor 2 (TLR2). IL-10-induced increase in proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulated LOX-1 as well as TLR2 inflammatory responses. Under stress conditions, phosphorylation of sterol regulatory element binding protein 1c (SREBP 1c) was prevented by IL-10. The latter also prevented the generation of OxPCs and reduced their ratio (OxPCs/PCs) during injury. LOX-1 activation also promoted SREBP1c-mediated TGF-βRII expression which was inhibited by IL-10. Both fragmented and non-fragmented OxPCs were elevated during I/R and this effect was attenuated by IL-10. The largest impact (two-threefold change at log) was on PAzPC, (1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine)-a fragmented OxPC. Thus it appears that among different OxPCs, IL-10 significantly reduces a single molecule (PAzPC)-mediated lipid metabolic responses in cardiomyocytes thereby mitigating inflammation and cell death.
氧化磷脂（OxPLs）在多种生理和病理状态下促进炎症以及低密度脂蛋白（LDL）的摄取。鉴于细胞因子 IL-10 的抗炎作用，我们研究了其对氧化磷脂酰胆碱（OxPC）的产生以及在整体心肌缺血/再灌注（I/R）损伤中的脂质代谢反应的调节作用。1-棕榈酰基-2-（5-氧代戊酰基）-sn-甘油-3-磷酸胆碱（POVPC）增加了 OxPCs 水平，促进了氧化应激（OS）和细胞死亡。OxPCs 介导的 OS 导致氧化型低密度脂蛋白受体 1（LOX-1）激活，并上调了 Toll 样受体 2（TLR2）的表达。IL-10 诱导的前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）的增加负调节 LOX-1 和 TLR2 炎症反应。在应激条件下，IL-10 阻止了固醇调节元件结合蛋白 1c（SREBP 1c）的磷酸化。后者还防止了 OxPCs 的产生，并在损伤过程中降低了它们的比率（OxPCs/PCs）。LOX-1 的激活还促进了 SREBP1c 介导的 TGF-βRII 表达，而 IL-10 抑制了这种表达。在 I/R 期间，LOX-1 激活还增加了片段化和非片段化 OxPCs 的产生，而 IL-10 则减弱了这种作用。影响最大的是（在对数上有两到三倍的变化）是 PAzPC（1-棕榈酰基-2-齐墩酰基-sn-甘油-3-磷酸胆碱）-一种片段化的 OxPC。因此，似乎在不同的 OxPCs 中，IL-10 显著降低了单个分子（PAzPC）介导的心肌细胞中的脂质代谢反应，从而减轻了炎症和细胞死亡。
