Journal article
Brain TACE (Tumor Necrosis Factor-α-Converting Enzyme) Contributes to Sympathetic Excitation in Heart Failure Rats
Hypertension (Dallas, Tex. 1979), Vol.74(1), pp.63-72
07/2019
DOI: 10.1161/HYPERTENSIONAHA.119.12651
PMCID: PMC6639045
PMID: 31154904
Abstract
TNF-α (tumor necrosis factor-α) is initially synthesized as a transmembrane protein that is cleaved by TACE (TNF-α-converting enzyme) to release soluble TNF-α. The elevated level of TNF-α in the brain and circulation in heart failure (HF) suggests an increase in the TACE-mediated ectodomain shedding process. The present study sought to determine whether TACE is upregulated in cardiovascular/autonomic brain regions like subfornical organ and hypothalamic paraventricular nucleus in rats with ischemia-induced HF and whether TACE plays a role in TNF-α-driven sympathetic excitation. We found that TACE was expressed throughout the subfornical organ and paraventricular nucleus, with significantly higher levels in HF than in sham-operated (Sham) rats. Intracerebroventricular injection of recombinant TACE induced a mild increase in blood pressure, heart rate, and renal sympathetic nerve activity that peaked at 15 to 20 minutes in both Sham and HF rats. HF rats had a secondary prolonged increase in these variables that was prevented by the TNF-α inhibitor SPD304. Intracerebroventricular administration of the TACE inhibitor TNF-alpha protease inhibitor 1 decreased blood pressure, heart rate, and renal sympathetic nerve activity in Sham and HF rats, with an exaggerated reduction in heart rate and renal sympathetic nerve activity in the HF rats. Direct microinjection of TACE or TNF-alpha protease inhibitor 1 into paraventricular nucleus or subfornical organ of Sham and HF rats elicited blood pressure, heart rate, and renal sympathetic nerve activity responses similar to intracerebroventricular TACE or TNF-alpha protease inhibitor 1. Intracerebroventricular infusion of Ang II (angiotensin II) and IL (interleukin)-1β increased TACE expression in subfornical organ and paraventricular nucleus of normal rats. These data suggest that a TACE-mediated increase in soluble TNF-α in the brain contributes to sympathetic excitation in HF.
Details
- Title: Subtitle
- Brain TACE (Tumor Necrosis Factor-α-Converting Enzyme) Contributes to Sympathetic Excitation in Heart Failure Rats
- Creators
- Yang Yu - From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of MedicineYiling Cao - From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of MedicineBalyssa Bell - From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of MedicineXiaolei Chen - From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of MedicineRobert M Weiss - From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of MedicineRobert B Felder - Veterans Affairs Medical Center, Iowa City, IA (R.B.F.)Shun-Guang Wei - Neuroscience Graduate Program (S.-G.W.), University of Iowa Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.74(1), pp.63-72
- DOI
- 10.1161/HYPERTENSIONAHA.119.12651
- PMID
- 31154904
- PMCID
- PMC6639045
- NLM abbreviation
- Hypertension
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Publisher
- United States
- Grant note
- S10 OD019941 / NIH HHS R01 HL073986 / NHLBI NIH HHS R01 HL139521 / NHLBI NIH HHS
- Language
- English
- Date published
- 07/2019
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984065483802771
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