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.
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Acknowledgements
The authors thank all the technicians from the animal facilities of the Plateformes Mutualisées de l’Institut du Médicament (P-MIM-UMS3612 CNRS-US25 INSERM), Faculté de Pharmacie, Université de Paris; the Small Animals Platform of the Cochin Institute for Echo-Doppler assessment and Life Imaging, Université de Paris (Plateforme Imageries du Vivant-PIV-UMRS1016 INSERM) for micro-CT assessment. The authors also thank Lofti Slimani (EA2496 and PIV, Paris, France) for his advice, and Anna Lokajczyk, Amayelle Rey, Astrid De La Roche and Teddy Leguillier (INSERM UMRS-1140, Paris, France) for their technical assistance. A.D. was supported by funds from the French Ministry of Research and Technology. This work was funded by grants from INSERM, the Université de Paris and FRM (DGE20111123012). The authors declare no conflicts of interest.
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Figure S1 Targeting endothelial TXNIP protects endothelium-independent mesenteric artery reactivity induced by metabolic disorders. (A–D) Reactivity of mesenteric arteries from siSCR- or siTXNIP-treated mice fed the HFHPLC diet (n = 6‒9/group). Results are expressed as means ± SEM and were analysed by two-way ANOVA, followed by a Bonferroni post hoc test. *p ≤ 0.05 (A) Concentration-response curves of contraction in response to phenylephrine. (B) Concentration-response curves for acetylcholine. (C) Concentration-response curves for acetylcholine with L-NAME pre-treatment. (D) Concentration-response curves for acetylcholine with NO donor sodium nitroprusside (SNP) pre-treatment (TIFF 14094 kb)
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Domingues, A., Boisson-Vidal, C., Marquet de Rouge, P. et al. Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation. Angiogenesis 23, 249–264 (2020). https://doi.org/10.1007/s10456-019-09704-x
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DOI: https://doi.org/10.1007/s10456-019-09704-x