| Autor: |
Lin, Yueh-Chien, Swendeman, Steven, Moreira, Irina S., Ghosh, Avishek, Kuo, Andrew, Rosário-Ferreira, Nícia, Guo, Shihui, Culbertson, Alan, Levesque, Michel V., Cartier, Andreane, Seno, Takahiro, Schmaier, Alec, Galvani, Sylvain, Inoue, Asuka, Parikh, Samir M., FitzGerald, Garret A., Zurakowski, David, Liao, Maofu, Flaumenhaft, Robert, Gümüş, Zeynep H. |
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| Zdroj: |
Science Signaling; 2/20/2024, Vol. 17 Issue 824, p1-17, 17p |
| Abstrakt: |
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. Editor's summary: Endothelial cell function is enhanced by bioactive lipids such as prostacyclin and sphingosine 1-phosphate (S1P) when bound to its chaperone apolipoprotein M (ApoM). Lin et al. generated a fusion protein called A1M to promote both S1P and prostacyclin signaling. A1M consisted of ApoM and ApoA1, a structural component of high-density lipoprotein (HDL) that stabilizes prostacyclin. When bound to S1P or a prostacyclin analog, A1M suppressed inflammation and increased the barrier function of cultured endothelial cells. In mouse models of acute or systemic inflammation, S1P-loaded A1M suppressed neutrophil infiltration, increases in circulating proinflammatory factors, and cytokine storm. The ApoA1 moiety of A1M therefore provides additional benefits over previously engineered S1P chaperones. —Wei Wong [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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