Yueh-Chien Lin, Steven Swendeman, Irina S. Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário-Ferreira, Shihui Guo, Alan Culbertson, Michel V. Levesque, Andreane Cartier, Takahiro Seno, Alec Schmaier, Sylvain Galvani, Asuka Inoue, Samir M. Parikh, Garret A. FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H. Gümüş, Timothy Hla
{"title":"设计高密度脂蛋白颗粒可增强内皮屏障功能并抑制炎症。","authors":"Yueh-Chien Lin, Steven Swendeman, Irina S. Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário-Ferreira, Shihui Guo, Alan Culbertson, Michel V. Levesque, Andreane Cartier, Takahiro Seno, Alec Schmaier, Sylvain Galvani, Asuka Inoue, Samir M. Parikh, Garret A. FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H. Gümüş, Timothy Hla","doi":"10.1126/scisignal.adg9256","DOIUrl":null,"url":null,"abstract":"<div >High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation\",\"authors\":\"Yueh-Chien Lin, Steven Swendeman, Irina S. Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário-Ferreira, Shihui Guo, Alan Culbertson, Michel V. Levesque, Andreane Cartier, Takahiro Seno, Alec Schmaier, Sylvain Galvani, Asuka Inoue, Samir M. Parikh, Garret A. FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H. Gümüş, Timothy Hla\",\"doi\":\"10.1126/scisignal.adg9256\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. 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Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation
High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.
期刊介绍:
"Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets.
The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment.
In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.