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Chronic isoprenaline/phenylephrine vs. exclusive isoprenaline stimulation in mice: critical contribution of alpha1-adrenoceptors to early cardiac stress responses : original contribution

Hyperactivity of the sympathetic nervous system is a major driver of cardiac remodeling, exerting its effects through both α-, and β-adrenoceptors (α-, β-ARs). As the relative contribution of subtype α1-AR to cardiac stress responses remains poorly investigated, we subjected mice to either subcutane...

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Main Authors: Dewenter, Matthias (Author) , Pan, Jianyuan (Author) , Knödler, Laura-Louise (Author) , Tzschöckel, Niklas (Author) , Henrich, Julian (Author) , Cordero, Julio (Author) , Dobreva, Gergana (Author) , Lutz, Susanne (Author) , Backs, Johannes (Author) , Wieland, Thomas (Author) , Vettel, Christiane (Author)
Format: Article (Journal)
Language:English
Published: 14 March 2022
In: Basic research in cardiology
Year: 2022, Volume: 117, Pages: 1-23
ISSN:1435-1803
DOI:10.1007/s00395-022-00920-z
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1007/s00395-022-00920-z
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Author Notes:Matthias Dewenter, Jianyuan Pan, Laura Knödler, Niklas Tzschöckel, Julian Henrich, Julio Cordero, Gergana Dobreva, Susanne Lutz, Johannes Backs, Thomas Wieland, Christiane Vettel
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Summary:Hyperactivity of the sympathetic nervous system is a major driver of cardiac remodeling, exerting its effects through both α-, and β-adrenoceptors (α-, β-ARs). As the relative contribution of subtype α1-AR to cardiac stress responses remains poorly investigated, we subjected mice to either subcutaneous perfusion with the β-AR agonist isoprenaline (ISO, 30 mg/kg × day) or to a combination of ISO and the stable α1-AR agonist phenylephrine (ISO/PE, 30 mg/kg × day each). Telemetry analysis revealed similar hemodynamic responses under both ISO and ISO/PE treatment i.e., permanently increased heart rates and only transient decreases in mean blood pressure during the first 24 h. Echocardiography and single cell analysis after 1 week of exposure showed that ISO/PE-, but not ISO-treated animals established α1-AR-mediated inotropic responsiveness to acute adrenergic stimulation. Morphologically, additional PE perfusion limited concentric cardiomyocyte growth and enhanced cardiac collagen deposition during 7 days of treatment. Time-course analysis demonstrated a diverging development in transcriptional patterns at day 4 of treatment i.e., increased expression of selected marker genes Xirp2, Nppa, Tgfb1, Col1a1, Postn under chronic ISO/PE treatment which was either less pronounced or absent in the ISO group. Transcriptome analyses at day 4 via RNA sequencing demonstrated that additional PE treatment caused a marked upregulation of genes allocated to extracellular matrix and fiber organization along with a more pronounced downregulation of genes involved in metabolic processes, muscle adaptation and cardiac electrophysiology. Consistently, transcriptome changes under ISO/PE challenge more effectively recapitulated early transcriptional alterations in pressure overload-induced experimental heart failure and in human hypertrophic cardiomyopathy.
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Gesehen am 30.05.2023
Physical Description:Online Resource
ISSN:1435-1803
DOI:10.1007/s00395-022-00920-z

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