Alison Domingues1, Catherine Boisson-Vidal1, Perrine Marquet de Rouge1, Blandine Dizier1, Jérémy Sadoine2, Virginie Mignon3, Emilie Vessières4, Daniel Henrion4, Virginie Escriou5, Pascal Bigey5, Catherine Chaussain2,6, David M Smadja1,7, Valérie Nivet-Antoine8,9. 1. INSERM 1140, Innovative Therapies in Haemostasis, Faculty of Pharmacy, Université de Paris, 75006, Paris, France. 2. EA 2496, Laboratory of Orofacial Pathologies, Imaging and Biotherapies, Dental School, Université de Paris, 92120, Montrouge, France. 3. PTICM, CNRS, INSERM 3612, Université de Paris, 75006, Paris, France. 4. CNRS, INSERM 1083, MITOVASC, Université Angers, 49045, Angers, France. 5. CNRS, Unité de Technologies Chimiques et Biologiques pour la santé (UTCBS), UMR 8258, INSERM 1022, Université de Paris, Chimie Paris Tech, 75006, Paris, France. 6. Odontology Department, AP-HP, Bretonneau Hospital, 75018, Paris, France. 7. Service d'Hématologie et Laboratoire de Recherches Biochirugicales (Fondation Carpentier), AH-HP, Georges Pompidou European Hospital, 75015, Paris, France. 8. INSERM 1140, Innovative Therapies in Haemostasis, Faculty of Pharmacy, Université de Paris, 75006, Paris, France. valerie.nivet-antoine@parisdescartes.fr. 9. Clinical Biochemistry Department, AP-HP, Necker Hospital, 75015, Paris, France. valerie.nivet-antoine@parisdescartes.fr.
Abstract
INTRODUCTION: 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.
INTRODUCTION: 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.