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

Abstract : Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biologic functions, the contribution of endothelial TXNIP has not been well defined. To investigate the endothelial function of TXNIP, we generated a TXNIP knockout mouse on the Cdh5-cre background (TXNIPfl/fl cdh5(cre)). Control (TXNIPfl/fl) and TXNIPfl/fl cdh5(cre) mice were fed a high protein-low carbohydrate (HP-LC) diet for 3 mo to induce metabolic stress. We found that TXNIPfl/fl and TXNIPfl/fl cdh5(cre) 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 endothelial TXNIP expression with regard to arterial structure and function. TXNIPfl/fl cdh5(cre) 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 came with lower oxidative stress and lower inflammation, with a reduced NLRP3 inflammasome expression, leading to a decrease in cleaved IL-1 beta. 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 a key role for endothelial TXNIP in arterial impairments induced by metabolic stress, making endothelial TXNIP a potential therapeutic target.
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https://hal-cnrs.archives-ouvertes.fr/hal-03292048
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Submitted on : Tuesday, July 20, 2021 - 10:29:31 AM
Last modification on : Tuesday, October 19, 2021 - 11:02:05 AM

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Tatiana Bedarida, Alison Domingues, Stephanie Baron, Chrystophe Ferreira, Francoise Vibert, et al.. Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo. FASEB Journal, Federation of American Society of Experimental Biology, 2018, 32 (6), pp.3108-3118. ⟨10.1096/fj.201700856RRR⟩. ⟨hal-03292048⟩

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