Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation

Area of Science:

• Biochemistry
• Molecular Biology
• Vascular Biology

Background:

• High-density lipoprotein (HDL) nanoparticles are known to improve endothelial cell (EC) function and reduce inflammation.
• The therapeutic potential of HDL in treating EC dysfunction remains underexplored.

Purpose of the Study:

• To investigate the potential of a novel fusion protein, ApoA1-ApoM (A1M), in enhancing endothelial barrier function and suppressing inflammation.
• To characterize the S1P-binding and signaling capabilities of A1M.

Main Methods:

• Construction and characterization of the ApoA1-ApoM (A1M) fusion protein.
• Molecular dynamics simulations to assess S1P-bound ApoM moiety's interaction with EC surface receptors.
• In vitro studies using human umbilical vein ECs to evaluate A1M-S1P's effect on barrier function and inflammation.
• In vivo studies in mice to assess A1M-S1P's efficacy in sterile inflammation and LPS-induced endotoxemia models.

Main Results:

• A1M forms HDL-like particles, binds S1P, and activates EC surface receptors.
• A1M-S1P treatment enhanced EC barrier function and suppressed cytokine-induced inflammation in vitro.
• A1M-S1P injection reduced neutrophil influx and inflammatory mediator secretion in mice during sterile inflammation.
• Systemic A1M administration increased circulating HDL-bound S1P and suppressed inflammation in a murine endotoxemia model.

Conclusions:

• ApoA1-ApoM fusion protein demonstrates significant potential in improving endothelial barrier function.
• A1M-S1P therapy can effectively mitigate inflammatory responses, including cytokine storm.
• A1M administration may offer a novel therapeutic strategy to enhance vascular endothelium resilience.