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Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation

By Alison Domingues, Catherine Boisson-Vidal, Perrine Marquet de Rouge, Blandine Dizier, Jérémy Sadoine, Virginie Mignon, Emilie Vessières, Daniel Henrion, Virginie Escriou, Pascal Bigey, Catherine Chaussain, David Smadja and Valérie NIVET-ANTOINE

Abstract

International audienceINTRODUCTION:Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biological functions, the contribution of endothelial TXNIP has not been well-defined in regards to endothelial and vascular function or in post-ischemic revascularisation. We postulated that inhibition of endothelial TXNIP with siRNA or in a Cre-LoxP system could be involved in protection from high fat, high protein, low carbohydrate (HFHPLC) diet-induced oxidative stress and endothelial dysfunction, leading to vascular damage and impaired revascularisation in vivo.METHODS AND RESULTS:To investigate the role of endothelial TXNIP, the TXNIP gene was deleted in endothelial cells using anti-TXNIP siRNA treatment or the Cre-LoxP system. Murine models were fed a HFHPLC diet, known to induce metabolic disorders. Endothelial TXNIP targeting resulted in protection against metabolic disorder-related endothelial oxidative stress and endothelial dysfunction. This protective effect mitigates media cell loss induced by metabolic disorders and hampered metabolic disorder-related vascular dysfunction assessed by aortic reactivity and distensibility. In aortic ring cultures, metabolic disorders impaired vessel sprouting and this alteration was alleviated by deletion of endothelial TXNIP. When subjected to ischemia, mice fed a HFHPLC diet exhibited defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. However, reducing endothelial TXNIP rescued metabolic disorder-related impairment of ischemia-induced revascularisation.CONCLUSION:Collectively, these results show that targeting endothelial TXNIP in metabolic disorders is essential to maintaining endothelial function, vascular function and improving ischemia-induced revascularisation, making TXNIP a potential therapeutic target for therapy of vascular complications related to metabolic disorders

Topics: Arterial damage, Endothelial dysfunction, Metabolic disorders, Oxidative stress, Post-ischemic revascularisation, TXNIP, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Publisher: 'Springer Science and Business Media LLC'
Year: 2020
DOI identifier: 10.1007/s10456-019-09704-x
OAI identifier: oai:HAL:inserm-02429278v1
Provided by: HAL-Inserm
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