Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Elshaer, Sally L., Mohamed, Islam N., Coucha, Maha, Altantawi, Sara, Eldahshan, Wael, Bartasi, Megan L., Shanab, Ahmed Y., Lorys, Renee, El-Remessy, Azza B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618075/
https://www.ncbi.nlm.nih.gov/pubmed/28661427
http://dx.doi.org/10.3390/antiox6030047
_version_ 1783267106785067008
author Elshaer, Sally L.
Mohamed, Islam N.
Coucha, Maha
Altantawi, Sara
Eldahshan, Wael
Bartasi, Megan L.
Shanab, Ahmed Y.
Lorys, Renee
El-Remessy, Azza B.
author_facet Elshaer, Sally L.
Mohamed, Islam N.
Coucha, Maha
Altantawi, Sara
Eldahshan, Wael
Bartasi, Megan L.
Shanab, Ahmed Y.
Lorys, Renee
El-Remessy, Azza B.
author_sort Elshaer, Sally L.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5618075
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-56180752017-09-29 Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia Elshaer, Sally L. Mohamed, Islam N. Coucha, Maha Altantawi, Sara Eldahshan, Wael Bartasi, Megan L. Shanab, Ahmed Y. Lorys, Renee El-Remessy, Azza B. Antioxidants (Basel) Article 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. MDPI 2017-06-29 /pmc/articles/PMC5618075/ /pubmed/28661427 http://dx.doi.org/10.3390/antiox6030047 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Elshaer, Sally L.
Mohamed, Islam N.
Coucha, Maha
Altantawi, Sara
Eldahshan, Wael
Bartasi, Megan L.
Shanab, Ahmed Y.
Lorys, Renee
El-Remessy, Azza B.
Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia
title Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia
title_full Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia
title_fullStr Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia
title_full_unstemmed Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia
title_short Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia
title_sort deletion of txnip mitigates high-fat diet-impaired angiogenesis and prevents inflammation in a mouse model of critical limb ischemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618075/
https://www.ncbi.nlm.nih.gov/pubmed/28661427
http://dx.doi.org/10.3390/antiox6030047
work_keys_str_mv AT elshaersallyl deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT mohamedislamn deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT couchamaha deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT altantawisara deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT eldahshanwael deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT bartasimeganl deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT shanabahmedy deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT lorysrenee deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia
AT elremessyazzab deletionoftxnipmitigateshighfatdietimpairedangiogenesisandpreventsinflammationinamousemodelofcriticallimbischemia