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Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats
Journal article   Open access   Peer reviewed

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

Yang Yu, Baojian Xue, Nafis Md Irfan, Terry Beltz, Robert M Weiss, Alan Kim Johnson, Robert B Felder and Shun-Guang Wei
Frontiers in physiology, Vol.13, 1052304
11/09/2022
DOI: 10.3389/fphys.2022.1052304
PMCID: PMC9682140
PMID: 36439267
url
https://doi.org/10.3389/fphys.2022.1052304View
Published (Version of record) Open Access

Abstract

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.
 Inflammation Physiology ADAM17 hypothalamic paraventricular nucleus myocardial infarction sympathetic nervous system tumor necrosis factor-α

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