Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis

Abstract

Circulating lactate levels are a critical biomarker for sepsis and are positively correlated with sepsis-associated mortality. We investigated whether lactate plays a biological role in causing endothelial barrier dysfunction in sepsis. We showed that lactate causes vascular permeability and worsens organ dysfunction in CLP sepsis. Mechanistically, lactate induces ERK-dependent activation of calpain1/2 for VE-cadherin proteolytic cleavage, leading to the enhanced endocytosis of VE-cadherin in endothelial cells. In addition, we found that ERK2 interacts with VE-cadherin and stabilizes VE-cadherin complex in resting endothelial cells. Lactate-induced ERK2 phosphorylation promotes ERK2 disassociation from VE-cadherin. In vivo suppression of lactate production or genetic depletion of lactate receptor GPR81 mitigates vascular permeability and multiple organ injury and improves survival outcome in polymicrobial sepsis. Our study reveals that metabolic cross-talk between glycolysis-derived lactate and the endothelium plays a critical role in the pathophysiology of sepsis.

Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction

“…( 35 ) unraveled that lactate production by lactate dehydrogenase A (LDHA) promotes cardiac myocyte hypertrophy. We recently observed that extracellular lactate directly impairs endothelial cell function during sepsis/septic shock and systemic administration of lactate inhibitor attenuates endothelial cell injury during sepsis ( 36 ). In the present study, we demonstrate that inhibiting lactate production markedly attenuated MI-induced cardiac dysfunction and cardiac fibrosis in mice.…”

Smart Lipid Nanoparticle that Remodels Tumor Microenvironment for Activatable H2S Gas and Photodynamic Immunotherapy

“…To investigate whether the excessive H 2 S released by 1 -JK-PS-FA in tumor cells could regulate the vascular endothelial conditions, the expression of VE-cadherin, claudin-5, and phalloidin (three major proteins in vascular endothelial cells that regulate endothelial vascular permeability) , was first examined using a transwell system (Figure c). Immunofluorescence staining revealed substantial loss and disruption of both VE-cadherin and claudin-5 expressions in HUVECs (cultured in the lower chamber), while there was obvious upregulation of the phalloidin expression in HUVECs when HeLa cells (in the upper chamber) were incubated with 1 -JK-PS-FA (Figure d).…”

Targeting hexokinase 1 alleviates NLRP3‐mediated inflammation in apical periodontitis: A laboratory investigation

“…2‐Deoxy‐ d ‐glucose, an analog of glucose, affects the metabolism of the rate‐limiting enzyme HK and inhibits glycolysis (Wang, Zhang et al, 2022; Yang et al, 2022). Following dose–response treatment with 2‐DG in LPS‐treated RAW264.7 cells, the expression levels of NLRP3, pro‐caspase‐1 and pro‐IL‐lβ were significantly downregulated, and there was a dramatic decrease in the expression of HK1 (Figure 7 and Table S7).…”