LACTATE IMPAIRS VASCULAR PERMEABILITY BY INHIBITING HSPA12B EXPRESSION VIA GPR81-DEPENDENT SIGNALING IN SEPSIS
Min Fan, Kun Yang, Xiaohui Wang
1Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
Shock (Augusta, Ga.)
|October 18, 2022
Summary
High lactate levels worsen sepsis by increasing vascular permeability. This study shows lactate disrupts endothelial cell junctions via HSPA12B and GPR81 signaling, contributing to organ failure in sepsis.
Area of Science:
- Biomedical Science
- Molecular Biology
- Pathophysiology
Background:
- Sepsis causes vascular integrity loss, leading to organ failure.
- Elevated circulating lactate levels correlate with increased sepsis mortality.
Purpose of the Study:
- To investigate lactate's role in sepsis-induced endothelial barrier dysfunction.
- To elucidate the molecular mechanisms involving HSPA12B and GPR81.
Main Methods:
- Polymicrobial sepsis induced via cecal ligation and puncture (CLP) in mice.
- Lactic acid administration and GPR81 inhibition (3OBA) used to assess effects.
- Vascular permeability measured by Evans blue assay; protein expression analyzed.
Main Results:
- Lactate administration increased vascular permeability in septic mice.
- Lactate decreased expression of VE-cadherin, claudin 5, and ZO-1 in endothelial cells.
- Lactate reduced HSPA12B expression, promoting VE-cadherin endocytosis; GPR81 inhibition reversed these effects.
Conclusions:
- Lactate promotes vascular hyperpermeability in sepsis by disrupting endothelial cell junctions.
- The signaling pathways involving HSPA12B and GPR81 mediate lactate's detrimental effects on vascular integrity.
- Targeting lactate signaling may offer therapeutic strategies for sepsis-induced vascular dysfunction.
