Chen Gaoxian, Douglas Hunter F, Li Zhu, Cleveland William J, Balzer Claudius, Yannopoulos Demetris, Chen Ian Y, Obal Detlef, Riess Matthias L
Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA.
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Sci Rep. 2025 Apr 30;15(1):15170. doi: 10.1038/s41598-025-97079-z.
Ischemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a non-ionic triblock copolymer, has been proposed to mitigate I/R injury by stabilizing cell membranes. However, the underlying mechanisms remain incompletely understood, particularly concerning endothelial cell (EC) function and nitric oxide (NO) production. We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and ECs to elucidate the effects of P188 on cellular survival, function, and NO secretion under simulated I/R conditions. iPSC-CMs contractility and iPSC-ECs' NO production were assessed following exposure to P188. Further, an isolated heart model using Brown Norway rats subjected to I/R injury was utilized to evaluate the ex-vivo cardioprotective effects of P188, examining cardiac function and NO production, with and without the administration of a NO inhibitor. In iPSC-derived models, P188 significantly preserved CM contractile function and enhanced cell viability after hypoxia/reoxygenation. Remarkably, P188 treatment led to a pronounced increase in NO secretion in iPSC-ECs, a novel finding demonstrating endothelial protective effects beyond membrane stabilization. In the rat isolated heart model, administration of P188 during reperfusion notably improved cardiac function and reduced I/R injury markers. This cardioprotective effect was abrogated by NO inhibition, underscoring the pivotal role of NO. Additionally, a dose-dependent increase in NO production was observed in non-ischemic rat hearts treated with P188, further establishing the critical function of NO in P188 induced cardioprotection. In conclusion, our comprehensive study unveils a novel role of NO in mediating the protective effects of P188 against I/R injury. This mechanism is evident in both cellular models and intact rat hearts, highlighting the potential of P188 as a therapeutic agent against I/R injury. Our findings pave the way for further investigation into P188's therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.
缺血/再灌注（I/R）损伤是导致心脏事件相关发病率和死亡率的重要因素。泊洛沙姆188（P188）是一种非离子三嵌段共聚物，有人提出它可通过稳定细胞膜来减轻I/R损伤。然而，其潜在机制仍未完全明确，尤其是在内皮细胞（EC）功能和一氧化氮（NO）生成方面。我们利用人诱导多能干细胞（iPSC）衍生的心肌细胞（CM）和内皮细胞，来阐明P188在模拟I/R条件下对细胞存活、功能及NO分泌的影响。在暴露于P188后，评估iPSC-CM的收缩性和iPSC-EC的NO生成。此外，使用遭受I/R损伤的棕色挪威大鼠的离体心脏模型，来评估P188的体外心脏保护作用，在给予和不给予NO抑制剂的情况下，检测心脏功能和NO生成。在iPSC衍生模型中，P188在缺氧/复氧后显著保留了CM的收缩功能并提高了细胞活力。值得注意的是，P188处理导致iPSC-EC中NO分泌显著增加，这一新颖发现表明其内皮保护作用超出了膜稳定作用。在大鼠离体心脏模型中，再灌注期间给予P188显著改善了心脏功能并降低了I/R损伤标志物。这种心脏保护作用被NO抑制所消除，强调了NO的关键作用。此外，在用P188处理的非缺血大鼠心脏中观察到NO生成呈剂量依赖性增加，进一步证实了NO在P188诱导的心脏保护中的关键作用。总之，我们的综合研究揭示了NO在介导P188对I/R损伤的保护作用中的新作用。这一机制在细胞模型和完整大鼠心脏中均很明显，突出了P188作为抗I/R损伤治疗剂的潜力。我们的发现为进一步研究P188的治疗机制及其在临床环境中减轻I/R相关心脏功能障碍的潜在应用铺平了道路。
