Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation
Yueh‐Chien Lin, Steven Swendeman, Irina S. Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário‐Ferreira, Shihui Guo, Alan Culbertson, Michel V. Levesque, Andréane Cartier, Takahiro Seno, Alec A. Schmaier, Sylvain Galvani, Asuka Inoue, Samir M. Parikh, Garret A. FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H. Gümüş, Timothy Hla
Abstract
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.