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Antioxidants 2017, 6(3), 47; doi:10.3390/antiox6030047

Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia

Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 20912, USA
Augusta Biomedical Research Corporation, Charlie Norwood VA Medical Center, Downtown 6B-105, Augusta, GA 30912, USA
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editor: Masuko Ushio-Fukai
Received: 13 February 2017 / Revised: 25 May 2017 / Accepted: 23 June 2017 / Published: 29 June 2017
(This article belongs to the Special Issue ROS Derived from NADPH Oxidase (NOX) in Angiogenesis)
View Full-Text   |   Download PDF [3879 KB, uploaded 29 June 2017]   |  


Background: Previous work demonstrated that high-fat diet (HFD) triggered thioredoxin-interacting protein (TXNIP) and that silencing TXNIP prevents diabetes-impaired vascular recovery. Here, we examine the impact of genetic deletion of TXNIP on HFD-impaired vascular recovery using hind limb ischemia model. Methods: Wild type mice (WT, C57Bl/6) and TXNIP knockout mice (TKO) were fed either normal chow diet (WT-ND and TKO-ND) or 60% high-fat diet (WT-HFD and TKO-HFD). After four weeks of HFD, unilateral hind limb ischemia was performed and blood flow was measured using Laser doppler scanner at baseline and then weekly for an additional three weeks. Vascular density, nitrative stress, infiltration of CD68+ macrophages, and expression of inflammasome, vascular endothelial growth factor (VEGF), VEGF receptor-2 were examined by slot blot, Western blot and immunohistochemistry. Results: By week 8, HFD caused similar increases in weight, cholesterol and triglycerides in both WT and TKO. At week 4 and week 8, HFD significantly impaired glucose tolerance in WT and to a lesser extent in TKO. HFD significantly impaired blood flow and vascular density (CD31 labeled) in skeletal muscle of WT mice compared to ND but not in TKO. HFD and ischemia significantly induced tyrosine nitration, and systemic IL-1β and infiltration of CD68+ cells in skeletal muscle from WT but not from TKO. HFD significantly increased cleaved-caspase-1 and IL-1 β compared to ND. Under both ND, ischemia tended to increase VEGF expression and increased VEGFR2 activation in WT only but not TKO. Conclusion: Similar to prior observation in diabetes, HFD-induced obesity can compromise vascular recovery in response to ischemic insult. The mechanism involves increased TXNIP-NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome activation, nitrative stress and impaired VEGFR2 activation. Deletion of TXNIP restored blood flow, reduced nitrative stress and blunted inflammasome-mediated inflammation; however, it did not impact VEGF/VEGFR2 in HFD. Targeting TXNIP-NLRP3 inflammasome can provide potential therapeutic target in obesity-induced vascular complication. View Full-Text
Keywords: high-fat diet; hind-limb ischemia; vascular endothelial growth factor; thioredoxin interacting protein; inflammation high-fat diet; hind-limb ischemia; vascular endothelial growth factor; thioredoxin interacting protein; inflammation

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Elshaer, S.L.; Mohamed, I.N.; Coucha, M.; Altantawi, S.; Eldahshan, W.; Bartasi, M.L.; Shanab, A.Y.; Lorys, R.; El-Remessy, A.B. Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia. Antioxidants 2017, 6, 47.

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