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Geist, D.* ; Hönes, G.S.* ; Grund, S.C.* ; Pape, J.* ; Siemes, D.* ; Spangenberg, P.* ; Tolstik, E.* ; Dörr, S.* ; Spielmann, N. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Mittag, J.* ; Engel, D.R.* ; Führer, D.* ; Lorenz, K.* ; Moeller, L.C.*

Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice.

Thyroid, DOI: 10.1089/thy.2023.0683 (2024)

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Open Access Green as soon as Postprint is submitted to ZB.

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BACKGROUND: Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determine in vivo which TH receptor (TR), α or β, and which mode of TR action, canonical gene expression or DNA binding independent noncanonical action, mediate these effects. MATERIAL AND METHODS: We compared global TRα and TRβ knockout mice (TRα^KO; TRβ^KO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRα^GS; TRβ^GS). Hearts were studied with echocardiography at baseline and after seven weeks T3 treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice. RESULTS: T3 induced ventricular hypertrophy in WT and TRβ^KO mice, but not in TRα^KO mice. Hypertrophy was also induced in TRα^GS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRα^GS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRα^KO mice, demonstrating that TRβ could compensate for absence of TRα. CONCLUSION: T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRβ could substitute for canonical, but not noncanonical TRα action.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Echocardiography ; Heart Rate ; Hypertrophy ; Noncanonical Signaling ; Thyroid Hormone ; Thyroid Hormone Receptor; Protein-kinase-c; Tr-beta; Pathways; 3-kinase

ISSN (print) / ISBN 1050-7256

e-ISSN 1557-9077

Journal Thyroid

Publisher Mary Ann Liebert

Publishing Place 140 Huguenot Street, 3rd Fl, New Rochelle, Ny 10801 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)

Grants German Center for Diabetes Research (DZD)
German Federal Ministry of Education and Research
Ministry for Innovation, Science and Research of the Federal State of North Rhine Westphalia
BMBF-ERK-Casting)
German Ministry of Research and Education (BMBF
Faculty of Medicine, University of Duisburg-Essen
Deutsche Forschungsgemeinschaft (DFG)