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Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats

Tumor necrosis factor (TNF)-α converting enzyme (TACE) is a key metalloprotease mediating ectodomain shedding of a variety of inflammatory mediators, substrates, and growth factors. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contri...

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Autores principales: Yu, Yang, Xue, Baojian, Irfan, Nafis Md, Beltz, Terry, Weiss, Robert M, Johnson, Alan Kim, Felder, Robert B, Wei, Shun-Guang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682140/
https://www.ncbi.nlm.nih.gov/pubmed/36439267
http://dx.doi.org/10.3389/fphys.2022.1052304
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author Yu, Yang
Xue, Baojian
Irfan, Nafis Md
Beltz, Terry
Weiss, Robert M
Johnson, Alan Kim
Felder, Robert B
Wei, Shun-Guang
author_facet Yu, Yang
Xue, Baojian
Irfan, Nafis Md
Beltz, Terry
Weiss, Robert M
Johnson, Alan Kim
Felder, Robert B
Wei, Shun-Guang
author_sort Yu, Yang
collection PubMed
description Tumor necrosis factor (TNF)-α converting enzyme (TACE) is a key metalloprotease mediating ectodomain shedding of a variety of inflammatory mediators, substrates, and growth factors. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to sympathetic excitation in heart failure (HF). Here, we sought to determine whether central interventions in TACE activity attenuate neuroinflammation and improve cardiac function in heart failure. Myocardial infarction-induced HF or sham-operated (SHAM) rats were treated with bilateral paraventricular nucleus microinjection of a TACE siRNA or a 4-week intracerebroventricular (ICV) infusion of the TACE inhibitor TAPI-0. Compared with SHAM rats, scrambled siRNA-treated HF rats had higher TACE levels in the PVN along with increased mRNA levels of TNF-α, TNF-α receptor 1 and cyclooxygenase-2. The protein levels of TNF-α in cerebrospinal fluid and phosphorylated (p-) NF-κB p65 and extracellular signal-regulated protein kinase (ERK)1/2 in the PVN were also elevated in HF rats treated with scrambled siRNA. The expression of these inflammatory mediators and signaling molecules in the PVN of HF rats were significantly attenuated by TACE siRNA. Interestingly, the mRNA level of TNF-α receptor 2 in the PVN was increased in HF treated with TACE siRNA. Moreover, sympathetic excitation, left ventricular end-diastolic pressure, pulmonary congestion, and cardiac hypertrophy and fibrosis were reduced by PVN microinjection of TACE siRNA. A 4-week treatment with intracerebroventricular TAPI-0 had similar effects to ameliorate these variables in HF rats. These data indicate that interventions suppressing TACE activity in the brain mitigate neuroinflammation, sympathetic activation and cardiac dysfunction in HF rats.
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spelling pubmed-96821402022-11-24 Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats Yu, Yang Xue, Baojian Irfan, Nafis Md Beltz, Terry Weiss, Robert M Johnson, Alan Kim Felder, Robert B Wei, Shun-Guang Front Physiol Physiology Tumor necrosis factor (TNF)-α converting enzyme (TACE) is a key metalloprotease mediating ectodomain shedding of a variety of inflammatory mediators, substrates, and growth factors. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to sympathetic excitation in heart failure (HF). Here, we sought to determine whether central interventions in TACE activity attenuate neuroinflammation and improve cardiac function in heart failure. Myocardial infarction-induced HF or sham-operated (SHAM) rats were treated with bilateral paraventricular nucleus microinjection of a TACE siRNA or a 4-week intracerebroventricular (ICV) infusion of the TACE inhibitor TAPI-0. Compared with SHAM rats, scrambled siRNA-treated HF rats had higher TACE levels in the PVN along with increased mRNA levels of TNF-α, TNF-α receptor 1 and cyclooxygenase-2. The protein levels of TNF-α in cerebrospinal fluid and phosphorylated (p-) NF-κB p65 and extracellular signal-regulated protein kinase (ERK)1/2 in the PVN were also elevated in HF rats treated with scrambled siRNA. The expression of these inflammatory mediators and signaling molecules in the PVN of HF rats were significantly attenuated by TACE siRNA. Interestingly, the mRNA level of TNF-α receptor 2 in the PVN was increased in HF treated with TACE siRNA. Moreover, sympathetic excitation, left ventricular end-diastolic pressure, pulmonary congestion, and cardiac hypertrophy and fibrosis were reduced by PVN microinjection of TACE siRNA. A 4-week treatment with intracerebroventricular TAPI-0 had similar effects to ameliorate these variables in HF rats. These data indicate that interventions suppressing TACE activity in the brain mitigate neuroinflammation, sympathetic activation and cardiac dysfunction in HF rats. Frontiers Media S.A. 2022-11-09 /pmc/articles/PMC9682140/ /pubmed/36439267 http://dx.doi.org/10.3389/fphys.2022.1052304 Text en Copyright © 2022 Yu, Xue, Irfan, Beltz, Weiss, Johnson, Felder and Wei. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Yu, Yang
Xue, Baojian
Irfan, Nafis Md
Beltz, Terry
Weiss, Robert M
Johnson, Alan Kim
Felder, Robert B
Wei, Shun-Guang
Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats
title Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats
title_full Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats
title_fullStr Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats
title_full_unstemmed Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats
title_short Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats
title_sort reducing brain tace activity improves neuroinflammation and cardiac function in heart failure rats
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682140/
https://www.ncbi.nlm.nih.gov/pubmed/36439267
http://dx.doi.org/10.3389/fphys.2022.1052304
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