Engineered high-density lipoprotein particles that chaperone bioactive lipid mediators to combat endothelial dysfunction and thromboinflammation

Swendeman, S.; Lin, D.; Guo, S.; Culbertson, A.; Kuo, A.; Levesque, M.; Cartier, A.; Seno, T.; Schmaier, A.; Galvani, S.; Inoue, A.; Parikh, S.; FitzGerald, G. A.; Liao, M.; Flaumenhaft, R.; Hla, T.

doi:10.1101/2022.02.14.480375

bioRxiv · 10.1101/2022.02.14.480375

Engineered high-density lipoprotein particles that chaperone bioactive lipid mediators to combat endothelial dysfunction and thromboinflammation

Swendeman, S.·Lin, D.·Guo, S.·Culbertson, A.·Kuo, A.·Levesque, M.·Cartier, A.·Seno, T.·Schmaier, A.·Galvani, S.·Inoue, A.·Parikh, S.·FitzGerald, G. A.·Liao, M.·Flaumenhaft, R.·Hla, T.

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Abstract

High-density lipoprotein (HDL) particles suppress inflammation-induced tissue injury via vascular and myeloid cell-dependent mechanisms. As such, HDL-associated bioactive lipids such as sphingosine 1-phosphate (S1P) and prostacyclin (PGI2) signal via their respective G protein-coupled receptors on target cells to promote vascular endothelial function and suppress platelet and myeloid-dependent pathophysiology. Here we have constructed a fusion protein of apolipoprotein A1 (ApoA1) and apolipoprotein M (ApoM) (A1M) that forms HDL-like particles and chaperones S1P and Iloprost, stable PGI2 analog. The A1M/S1P complex activates S1P receptor-1 (S1PR1) as a Gi-biased agonist and attenuates the inflammation-induced NF{kappa}B pathway while A1M/Iloprost acts via IP receptor to inhibit platelet aggregation and promote endothelial barrier function. In addition to enhancing the endothelial barrier, A1M/S1P suppresses neutrophil influx, oxidative burst and inflammatory mediator secretion in a sterile inflammation model. We propose that A1M could be useful as a therapeutic to induce S1P and PGI2-dependent anti-inflammatory functions and suppress collateral tissue injury.

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Swendeman, S., Lin, D., Guo, S., Culbertson, A., Kuo, A., Levesque, M., Cartier, A., Seno, T., Schmaier, A., Galvani, S., Inoue, A., Parikh, S., FitzGerald, G. A., Liao, M., Flaumenhaft, R., Hla, T.. 2022-02-14. Engineered high-density lipoprotein particles that chaperone bioactive lipid mediators to combat endothelial dysfunction and thromboinflammation. https://doi.org/10.1101/2022.02.14.480375

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