Cardioprotection by poloxamer 188 is mediated through increased endothelial nitric oxide production

Gaoxian Chen; Hunter F Douglas; Zhu Li; William J Cleveland; Claudius Balzer; Demetris Yannopoulos; Ian Y Chen; Detlef Obal; Matthias L Riess

doi:10.1038/s41598-025-97079-z

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Cardioprotection by poloxamer 188 is mediated through increased endothelial nitric oxide production

Journal article

Open access

Peer reviewed

Cardioprotection by poloxamer 188 is mediated through increased endothelial nitric oxide production

Gaoxian Chen, Hunter F Douglas, Zhu Li, William J Cleveland, Claudius Balzer, Demetris Yannopoulos, Ian Y Chen, Detlef Obal and Matthias L Riess

Scientific reports, Vol.15(1), 15170

04/30/2025

DOI: 10.1038/s41598-025-97079-z

PMCID: PMC12043958

PMID: 40307302

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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 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.

Animals

Cardiotonic Agents - pharmacology

Cell Survival - drug effects

Endothelial Cells - drug effects

Endothelial Cells - metabolism

Humans

Induced Pluripotent Stem Cells - cytology

Induced Pluripotent Stem Cells - drug effects

Induced Pluripotent Stem Cells - metabolism

Male

Myocardial Reperfusion Injury - drug therapy

Myocardial Reperfusion Injury - metabolism

Myocardial Reperfusion Injury - pathology

Myocardial Reperfusion Injury - prevention & control

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - metabolism

Nitric Oxide - biosynthesis

Nitric Oxide - metabolism

Poloxamer - pharmacology

Rats

Rats, Inbred BN

Details

Title: Subtitle: Cardioprotection by poloxamer 188 is mediated through increased endothelial nitric oxide production
Creators: Gaoxian Chen - Stanford University
Hunter F Douglas - Vanderbilt University Medical Center
Zhu Li - Vanderbilt University Medical Center
William J Cleveland - Vanderbilt University Medical Center
Claudius Balzer - Vanderbilt University Medical Center
Demetris Yannopoulos - University of Minnesota
Ian Y Chen - Medical (Cardiology) and Radiology Services, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
Detlef Obal - University of Iowa
Matthias L Riess - Vanderbilt University
Resource Type: Journal article
Publication Details: Scientific reports, Vol.15(1), 15170
DOI: 10.1038/s41598-025-97079-z
PMID: 40307302
PMCID: PMC12043958
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Publisher: NATURE PORTFOLIO
Grant note: I01 BX003482 / BLRD VA Project BA 6287/1-1 / Deutsche Forschungsgemeinschaft 1232057-100-DHPFC TIP grant / Stanford Maternal and Child Health Research Institute Transformative Project Award (962204) / American Heart Association 5R01 HL123227 / NIH HHS R01 HL123227 / NHLBI NIH HHS
Language: English
Date published: 04/30/2025
Academic Unit: Anesthesia
Record Identifier: 9984815908302771

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