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

• Published in: The FASEB journal Vol. 32; no. 6; pp. 3108 - 3118
• Main Authors: Bedarida, Tatiana, Domingues, Alison, Baron, Stephanie, Ferreira, Chrystophe, Vibert, Francoise, Cottart, Charles-Henry, Paul, Jean-Louis, Escriou, Virginie, Bigey, Pascal, Gaussem, Pascale, Leguillier, Teddy, Nivet-Antoine, Valerie
• Format: Journal Article
• Language: English
• Published: United States Federation of American Society of Experimental Biology 01-06-2018
• Subjects: Animals; Aorta - metabolism; Aorta - pathology; arterial damage; Cardiology and cardiovascular system; Carrier Proteins - genetics; Carrier Proteins - metabolism; Diet, Carbohydrate-Restricted - adverse effects; Dietary Proteins - adverse effects; Dietary Proteins - pharmacology; Dyslipidemias - chemically induced; Dyslipidemias - genetics; Dyslipidemias - metabolism; Dyslipidemias - pathology; endothelial dysfunction; Glucose Intolerance - chemically induced; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose Intolerance - pathology; HP-LC diet; Human health and pathology; Inflammasomes - genetics; Inflammasomes - metabolism; inflammation; Life Sciences; Mice; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein - biosynthesis; Serpin E2 - biosynthesis; Stress, Physiological; Thioredoxins - genetics; Thioredoxins - metabolism; TXNIP; TXNIP; inflammation; arterial damage; endothelial dysfunction; HP-LC diet; RESVERATROL; OXIDATIVE STRESS; DIET; INFLAMMASOME ACTIVATION; INSULIN-RESISTANCE; DISEASE; MOUSE; SMOOTH-MUSCLE-CELLS; MICE; DYSFUNCTION
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201700856RRR

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 cdh5cre). Control (TXNIPfl/fl) and TXNIPfl/fl cdh5cre 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 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 endothelial TXNIP expression with 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 came with lower oxidative stress and lower 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 a key role for endothelial TXNIP in arterial impairments induced by metabolic stress, making endothelial TXNIP a potential therapeutic target.—Bedarida T., Domingues, A., Baron, S., Ferreira, C., Vibert, F., Cottart, C.‐H., Paul J.‐L., Escriou, V., Bigey, P., Gaussem, P., Leguillier, T., Nivet‐Antoine V. Reduced endothelial thioredoxin‐interacting protein protects arteries from damage induced by metabolic stress in vivo. FASEB J. 32, 3108–3118 (2018). www.fasebj.org