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Gender-specific mechanisms of cardiac dysfunction in obesity

English title Gender-specific mechanisms of cardiac dysfunction in obesity
Applicant Brink Marijke
Number 169996
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.10.2016 - 31.03.2021
Approved amount 297'080.00
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All Disciplines (7)

Discipline
Cardiovascular Research
Cellular Biology, Cytology
Pathophysiology
Endocrinology
Biochemistry
Physiology : other topics
Molecular Biology

Keywords (9)

heart disease; mammalian target of rapamycin; signal transduction; insulin-like growth factor; glucose metabolism; insulin; inflammation; autophagy; growth regulation

Lay Summary (German)

Lead
Die Prävalenz der Herzinsuffizienz mit erhaltener Auswurffraktion (HFpEF) hat stark zugenommen und zeigt eine schlechte Prognose. Die pathophysiologischen Mechanismen der HFpEF sind unzureichend bekannt und dadurch ist die Therapie im Wesentlichen empirisch. Unser Projekt möchte einen Beitrag leisten zum besseren Verständnis dieser Mechanismen und wird ins Besondere geschlechtsspezifische Aspekte analysieren.
Lay summary

Unser Forschungslabor hat Tiermodelle und Techniken entwickelt, welche es uns erlauben pathophysiologische und molekulare Mechanismen der diastolischen Dysfunktion zu analysieren. Da Frauen häufig betroffen sind und Adipositas ein Kofaktor in der Pathogenese der HFpEF ist, besteht unser Modell aus weiblichen Mäusen, welche nach einer Ovariektomie eine fett- und zuckerreiche Nahrung erhalten. Unsere molekularen Analysen zeigten die Veränderung metabolischer Signalwege nach Ovariektomie. In diesem Forschungsprojekt werden wir nun die geschlechtsspezifischen Mechanismen näher untersuchen.  Neben metabolische- (Stoffwechsel und Zellwachstum) stehen dabei Entzündungs-Mechanismen im Zentrum des Interesses. Wir analysieren diese Mechanismen sowohl in primären Zellkulturen als auch in Mausmodellen der Adipositas und Drucklast, da diese einen direkten Bezug haben zu den heute am häufigsten beobachteten klinischen Bedingungen. Wir führen unsere Studien mit männlichen und weiblichen Tieren durch und hoffen damit zu einer besseren Vorbeugung und zur Identifizierung neuer therapeutischen Targets bei beiden Geschlechtern beizutragen.

Direct link to Lay Summary Last update: 04.10.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Fatty acid-based monolayer culture to promote in vitro neonatal rat cardiomyocyte maturation
Isu Giuseppe, Diaz Diana Robles, Grussenmeyer Thomas, Gaudiello Emanuele, Eckstein Friedrich, Brink Marijke, Marsano Anna (2020), Fatty acid-based monolayer culture to promote in vitro neonatal rat cardiomyocyte maturation, in Biochimica et Biophysica Acta ({BBA}) - Molecular Cell Research, 1867(3), 118561-118561.
Neuregulin-1 triggers GLUT4 translocation and enhances glucose uptake independently of insulin receptor substrate and ErbB3 in neonatal rat cardiomyocytes
HeimPhilippe, MorandiChristian, BrouwerGian R, XuLifen, MontessuitChristoph, BrinkMarijke (2020), Neuregulin-1 triggers GLUT4 translocation and enhances glucose uptake independently of insulin receptor substrate and ErbB3 in neonatal rat cardiomyocytes, in Biochim Biophys Acta Mol Cell Res, 1867(3), 1-11.
Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure
De Keulenaer Gilles, Feyen Eline, Dugaucquier Lindsey, Shakeri Hadis, Shchendrygina Anastasia, Belenkov Yuri N, Brink Marijke, Vermeulen Zarha, Segers Vincent FM (2019), Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure, in Circulation: Heart Failure, 12(10), 1-15.
Moderate Modulation of Cardiac PGC-1α Expression Partially Affects Age-Associated Transcriptional Remodeling of the Heart
WhiteheadNatasha, GillJonathan F, BrinkMarijke, HandschinChristoph (2018), Moderate Modulation of Cardiac PGC-1α Expression Partially Affects Age-Associated Transcriptional Remodeling of the Heart, in Frontiers in Physiology, 9, 1-13.

Collaboration

Group / person Country
Types of collaboration
Markus Rüegg / Biozentrum Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Christtoph Handschin Switzerland (Europe)
- Publication
Gilles De Keulenaer / University of Antwerpen Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Duska Dragun / Charité Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Society of heart and vascular metabolism - 17th annual scientific sessions Poster Neuregulin-1 stimulates glucose uptake in neonatal rat cardiomyocytes 23.06.2019 Amsterdam, Netherlands Heim Philippe; Brink Marijke;
ESC Joint Meeting of the ESC Working Groups on Myocardial Function and Cellular Biology of the Heart Poster Neuregulin-1 enhances IGF-I-induced cardiomyocyte proliferation 09.05.2019 Napoli, Italy Heim Philippe; Brink Marijke;
ESC Heart Failure Winter Research Meeting 2019. Les Diablerets Poster Neuregulin-1 stimulates glucose uptake in neonatal rat cardiomyocytes by regulating GLUT4 translocation 23.01.2019 Les Diablerets, Switzerland Heim Philippe; Brouwer Gian Reto; Brink Marijke;
9th Ascona International Workshop on Cardiomyocyte Biology - Congressi Stefano Franscini, Monte Verità, Ascona Poster Neuregulin1β mediates glucose uptake in neonatal cardiomyocytes by a similar mechanism as insulin 22.04.2018 Ascona, Switzerland Heim Philippe; Brouwer Gian Reto; Brink Marijke;
9th Ascona International Workshop on Cardiomyocyte Biology 2018 Poster Sex-specific systemic and cardiac responses to obesity in mice 22.04.2018 Ascona, Switzerland Xu Lifen; Brouwer Gian Reto; Lebboukh Sonia; Brink Marijke;
LS2 - Cardiovascular Biology Meeting 2018 Talk given at a conference Neuregulin1β regulates glucose uptake in cardiomyocytes 15.03.2018 Fribourg, Switzerland Heim Philippe;
Advanced training seminars for physicians - The department of Cardiology and Angiology of the Hannover School of Medicine Individual talk Impact of mTORC1 and mTORC2 oncardiac hypertrophy and heart failure 27.11.2017 Hannover, Germany Brink Marijke;
34th ISHR-ES Meeting Talk given at a conference mTORC1 and mTORC2 preserve cardiac function by regulating metabolism and contractility 25.07.2017 Hamburg, Germany Brink Marijke;


Self-organised

Title Date Place
EMBO Workshop on Cardiomyocyte Biology 30.05.2021 Ascona, Switzerland

Associated projects

Number Title Start Funding scheme
204537 Neuregulin-induced cardioprotection in doxorubicin-treated xenograft models 01.10.2021 Project funding (Div. I-III)
116483 Regulation of protein turnover in cardiac muscle by the ubiquitin proteasome pathway 01.05.2007 Project funding (Div. I-III)
128782 R'equip grant for Visual Sonics Vevo 770 high resolution small animal ultrasound system 01.12.2009 R'EQUIP
135559 Cardiac pathways of protein and energy metabolism in health and disease 01.05.2011 Project funding (Div. I-III)

Abstract

Recent increases in physical inactivity and obesity are accompanied by an increased incidence of heart failure with preserved ejection fraction (HFpEF). While obesity and type 2-diabetes mellitus (T2DM) are thought to contribute to the pathophysiology of the diastolic dysfunction frequently observed in these patients, the underlying mechanisms are only poorly understood and therapy of HFpEF therefore remains highly empirical. Moreover, the mechanistic insights obtained to date are mainly based on studies with male mice and virtually nothing is known in about the pathophysiology in female. Because the disease is particularly frequent in the female population after menopause, the overall aim of our research is to identify novel gender-specific mechanisms that protect against diastolic dysfunction. The role of the distinct estrogen receptors in obesity-related cardiac dysfunction are not yet understood.The proposed project therefore has the following aims:Aim 1: To analyze the effects of gender and ovarian hormones on cardiac hemodynamics in obese mice.Aim 2: To analyze gender-specific mechanisms of cardiac dysfunction in high fat/high sucrose (HFD)-induced obesity.Aim 3: To analyze the role of the distinct estrogen receptors in regulating cardiac inflammation, metabolism and function after HFD feeding.We will use echocardiography, pressure volume loop analysis and the ex vivo working heart setup to analyze cardiac metabolism and hemodynamic function in male, female, and ovariectomized (OVX)-female mice after HFD feeding. In this model, we will evaluate inflammatory responses, fibrosis, energy metabolism and autophagy, titin phosphorylation and titin isoform expression as well as calcium handling proteins, and assess whether gender or ovarian hormones, by one or more of these cellular mechanisms, alter diastolic function. For the observed effects, we will evaluate if and how mTOR and the PKCs are implicated. Our anticipated new insights into the mechanisms that cause diastolic dysfunction in female and male models will hopefully contribute to stratified strategies that will increase the healthy lifespan of both genders.
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