Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo

Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biologic functions, the contribution of endothelial TXNIP has not beenwell defined. To investigate the endothelial function of TXNIP,we generated a TXNIP knockout mouse on the Cdh5-cre background (TXNIPfl/fl cdh5cre). Control (TXNIPfl/fl) and TXNIPfl/fl cdh5cremicewere fed a high protein-low carbohydrate (HP-LC) diet for 3mo to inducemetabolic stress. We found that TXNIPfl/fl and TXNIPfl/fl cdh5cre mice on an HP-LC diet displayed impaired glucose tolerance and dyslipidemia concretizing the metabolic stress induced. We evaluated the impact of this metabolic stress on mice with reduced endothelialTXNIP expressionwith regard to arterial structure and function.TXNIPfl/fl cdh5cre mice on an HP-LC diet exhibited less endothelial dysfunction than littermate mice on an HP-LC diet. These mice were protected from decreased aortic medial cell content, impaired aortic distensibility, and increased plasminogen activator inhibitor 1 secretion. This protective effect camewithloweroxidative stress andlower inflammation,with a reduced NLRP3 inflammasome expression, leading to a decrease in cleaved IL-1β.We also show the major role of TXNIP in inflammation with a knockdown model, using a TXNIP-specific, small interfering RNA included in a lipoplex.These findings demonstrate akey role for endothelialTXNIPin arterialimpairments inducedbymetabolic stress, making endothelial TXNIP a potential therapeutic target.