Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Fernandes Hollnagel, C.
Conservation of β2-adrenergic signaling in rat and human cardiomyocytes during heart failure
Humanmedizin; [ Diplomarbeit ] Medizinische Universität Graz; 2024. pp. 115
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Holzer Senka
- Rainer Peter
- Altmetrics:
- Abstract:
- Introduction: Beta-2 adrenergic (β2AR) signaling in heart failure remains an area of active investigation, presenting diverse insights. The dual nature of β2AR signaling, exhibiting both cardioprotective and cardiotoxic effects, remains incompletely understood. Moreover, the translational relevance of animal models to human data is yet to be fully established. Material and Methods: This thesis investigates the preservation of β2AR signaling in male rat and male and female human hearts during heart failure. To discern the intricacies of β2AR behavior, we utilized a hypertensive Dahl salt-sensitive rat model fed a high-salt-diet starting at 7 weeks (HSD, 8% NaCl) for 5 (early remodeling) and 10 to 12 (late remodeling) weeks. The control group comprised male Dahl salt-sensitive rats on a low-salt-diet (LSD, 0.3% NaCl). In addition, we had valuable access to donor and explanted human heart tissue with various degrees of cardiac remodeling. Phenotyping of rats as heart failure with Preserved Ejection Fraction (HFpEF) occurred through gravimetric analyses and echocardiography. Human subjects were categorized into HFpEF and heart failure with Reduced Ejection Fraction (HFrEF) groups based on echocardiography data provided by the Department of Cardiology. Cardiomyocytes were obtained through Langendorff isolation methods. Quantification of β2AR involved Immunocytochemistry (ICC), immunoblotting, and microarray techniques. Cells used for ICC were additionally stimulated with β-adrenergic agonist isoprenaline. Results: (1) Significant β2AR downregulation, particularly at a late remodeling time point, in the microarray and ICC analyses of the Dahl salt-sensitive rat model; (2) Conversely, rat immunoblots failed to reproduce this observation; (3) Comparable rates of β1AR and β2AR downregulation in rats in the ICC at a late remodeling timepoint; (4) Impaired rapid-ISO-induced β2AR downregulation in HSD Dahl salt-sensitive rats; (5) β2AR downregulation observed in human immunoblot for diastolic dysfunction, but not for dilated cardiomyopathy. Discussion: We conclude that β2AR downregulation occurs at a comparable rate to β1AR during late-stage cardiac remodeling in rats with systemic hypertension heart failure. In humans, superior downregulation was evident in patients with diastolic dysfunction compared to dilated cardiomyopathy. These insights suggest a specific adrenergic expression pattern depending on heart failure type, stage, and etiology. Future experiments, including translation to human tissue and analysis of β2AR downstream targets, promise additional molecular insights into β2AR signaling in humans during the development and progression of heart failure. Such insights may inform novel treatment strategies tailored to specific heart failure types, stages, and etiologies, contributing to the paradigm of personalized medicine.