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

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.