{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T22:53:42Z","timestamp":1782514422443,"version":"3.54.5"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T00:00:00Z","timestamp":1667952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL-139521 and HL-155091 (to S.-G. W.) HL-139575 (to A.K. J and B. X.)"],"award-info":[{"award-number":["HL-139521 and HL-155091 (to S.-G. W.) HL-139575 (to A.K. J and B. X.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Tumor necrosis factor (TNF)-\u03b1 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-\u03b1 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-\u03b1, TNF-\u03b1 receptor 1 and cyclooxygenase-2. The protein levels of TNF-\u03b1 in cerebrospinal fluid and phosphorylated (p-) NF-\u03baB 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-\u03b1 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.<\/jats:p>","DOI":"10.3389\/fphys.2022.1052304","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T06:55:16Z","timestamp":1667976916000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats"],"prefix":"10.3389","volume":"13","author":[{"given":"Yang","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baojian","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nafis Md","family":"Irfan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Beltz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan Kim","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B","family":"Felder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-Guang","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1126\/science.1214400","article-title":"Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE","volume":"335","author":"Adrain","year":"2012","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1042\/CS20020367","article-title":"Increased mRNA expression of tumour necrosis factor-alpha and its converting enzyme in circulating leucocytes of patients with acute myocardial infarction","volume":"105","author":"Akatsu","year":"2003","journal-title":"Clin. 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