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bioRxiv · 10.1101/2024.05.18.593838

Cardioprotection by Poloxamer 188 is Mediated through Increased Endothelial Nitric Oxide Production

Chen, G.·Douglas, H. F.·Li, Z.·Cleveland, W. J.·Balzer, C.·Yannopolous, D.·Chen, I. Y.-L.·Obal, D.·Riess, M. L.
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Abstract

Ischemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a nonionic 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 function and nitric oxide (NO) production. We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (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 P188s therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.

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Chen, G., Douglas, H. F., Li, Z., Cleveland, W. J., Balzer, C., Yannopolous, D., Chen, I. Y.-L., Obal, D., Riess, M. L.. 2024-05-20. Cardioprotection by Poloxamer 188 is Mediated through Increased Endothelial Nitric Oxide Production. https://doi.org/10.1101/2024.05.18.593838

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