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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)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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 (TRαKO; TRβKO) 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 (TRαGS; TRβGS). 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 TRβKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS 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 TRαKO 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Thyroid
Verlag Mary Ann Liebert
Verlagsort 140 Huguenot Street, 3rd Fl, New Rochelle, Ny 10801 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Förderungen 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)