CD226 deficiency promotes glutaminolysis and alleviates mitochondria damage in vascular endothelial cells under hemorrhagic shock

Abstract

Hemorrhagic shock (HS) is common in clinical emergencies, leading to millions of deaths each year globally. CD226 is a costimulatory adhesion molecule expressed on both immune cells and endothelial cells (ECs) to regulate their metabolic activity and function. As endothelial dysfunction occurs after HS, the roles CD226 plays in vascular EC metabolism were investigated. CD226 fl/fl Tek cre mice were adopted to achieve vascular EC-specific knockout of CD226, and subjected to HS modelling. Serum levels of crucial intermediate metabolites were evaluated through liquid chromatography-mass spectrometry analysis. Human umbilical vein ECs (HUVECs) were used to study the effects of CD226 under hypoxia in vitro. Seahorse analysis evaluated the cellular glycolysis and mitochondria bioenergetics. Results showed that CD226 deficiency in vascular ECs alleviated HSinduced intestinal damage and inflammatory response in mice. Animal studies indicated an improved energy metabolism when CD226 was knocked out in ECs after HS, as evidenced by enhanced glutamine-glutamate metabolism and decreased lactic acid levels. Glut-1 was upregulated in mouse vascular ECs after HS and HUVECs under hypoxia, combined with decreased CD226. Moreover, HUVECs with CD226 knockdown exhibited relieved mitochondrial damage and early apoptosis under hypoxia, whereas CD226 overexpression showed opposite effects. Seahorse analysis showed that downregulated CD226 significantly increased mitochondrial ATP production and glucose uptake in HUVECs under hypoxia. Additionally, Erk/PHD2 signaling-mediated HIF-1α/Glut-1 and HIF-2α/

Costimulatory CD226 Signaling Regulates Proliferation of Memory-like NK Cells in Healthy Individuals with Latent Mycobacterium tuberculosis Infection

“…It was not established if CD226 signaling modulates metabolism in NK cells. Recently, CD226 signaling was reported to promote glycolysis in endothelial cells [ 48 ]. Similarly, we noted diminished glycolysis in NK cells from LTBI+ people after CD226 blockade.…”

Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score

“…Using the UCSC genome browser [41] integrating information about interactions between GeneHancer regulatory elements and genes expression (see S4 Fig) , we identified CD226 as a strong biological candidate. CD226 codes for a glycoprotein expressed at the surface of several types of cells, including blood cell, and several studies have shown that it was associated with vascular endothelial dysfunction [42][43][44]. Genetic variants in CD226 have also been found associated with several blood cell traits including platelets, white blood cells (e.g.…”

Innate immunity and immunotherapy for hemorrhagic shock

“…CD226, a costimulatory adhesion molecule expressed on both immune and endothelial cells, can regulate immune metabolic activity and function ( 94 , 95 ). Recent studies have illustrated that CD226 deficiency in vascular endothelial cells can alleviate HS-induced intestinal damage and the inflammatory response ( 96 ). Emerging evidence shows that microRNAs play essential roles in pathophysiological responses by regulating inflammation and immunity ( 97 , 98 ).…”