Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effects on cardiovascular functions via S1P receptors, but its effects on cardiac I/R injury are not fully understood. Plasma lipidomics analysis by mass spectrometry revealed that sphingosine lipids, including sphingosine 1-phosphate (S1P), were significantly down-regulated following cardiac I/R injury in mice. The reduced S1P levels were also observed in the plasma of coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI) compared with those without PCI. We found that S1P exerted a cardioprotective effect via endothelial cell (EC)-S1PR1, whereas EC-S1PR2 displayed a detrimental effect on cardiac I/R. Our data showed that EC-specific loss-of-function significantly lessened inflammatory responses and diminished cardiac I/R injury, while EC-specific gain-of-function aggravated cardiac I/R injury. Mechanistically, EC-S1PR2 initiated excessive mitochondrial fission and elevated ROS production via RHO/ROCK1/DRP1 pathway, leading to NLRP3 inflammasome activation and subsequent cell pyroptosis, thereby exacerbating inflammation and I/R injuries. Furthermore, RGD-peptide magnetic nanoparticles packaging to specifically knockdown S1PR2 in endothelial cells significantly ameliorated cardiac I/R injury. Taken together, our investigations demonstrate that EC-S1PR2 induces excessive mitochondrial fission, which results in NLRP3 inflammasome activation and subsequently triggers cell pyroptosis, ultimately exacerbating inflammatory responses and aggravating heart injuries following I/R.

中文翻译：

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内皮 S1PR2 通过调节线粒体功能障碍、NLRP3 炎性体激活和细胞焦亡在心脏缺血再灌注损伤中发挥有害作用


1-磷酸鞘氨醇 (S1P) 是一种生物活性脂质分子，通过 S1P 受体对心血管功能产生多方面的影响，但其对心脏 I/R 损伤的影响尚不完全清楚。通过质谱法进行的血浆脂质组学分析显示，小鼠心脏缺血再灌注损伤后，鞘氨醇脂质（包括 1-磷酸鞘氨醇 (S1P)）显着下调。与未接受 PCI 的患者相比，经皮冠状动脉介入治疗 (PCI) 后的冠心病 (CHD) 患者血浆中 S1P 水平也有所降低。我们发现 S1P 通过内皮细胞 (EC)-S1PR1 发挥心脏保护作用，而 EC-S1PR2 对心脏 I/R 表现出有害影响。我们的数据表明，EC 特异性功能丧失显着减轻了炎症反应并减少了心脏 I/R 损伤，而 EC 特异性功能获得则加剧了心脏 I/R 损伤。从机制上讲，EC-S1PR2通过RHO/ROCK1/DRP1途径启动过度的线粒体裂变并增加ROS的产生，导致NLRP3炎性体激活和随后的细胞焦亡，从而加剧炎症和I/R损伤。此外，包装RGD-肽磁性纳米颗粒可特异性敲低内皮细胞中的S1PR2，显着改善心脏缺血再灌注损伤。综上所述，我们的研究表明，EC-S1PR2 诱导过度的线粒体裂变，导致 NLRP3 炎症小体激活，随后引发细胞焦亡，最终加剧炎症反应并加重 I/R 后的心脏损伤。