Dokument: Interorgan Crosstalk between the Heart and Adipose Tissue during Heart Failure Establishment

Titel:Interorgan Crosstalk between the Heart and Adipose Tissue during Heart Failure Establishment
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URN (NBN):urn:nbn:de:hbz:061-20200212-110052-5
Dokumententyp:Wissenschaftliche Abschlussarbeiten » Dissertation
Autor: Oenarto, Vici [Autor]
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Dateien vom 12.02.2020 / geändert 12.02.2020
Beitragende:Prof. Dr. Gödecke, Axel [Gutachter]
Prof. Dr. Fischer, Jens [Gutachter]
Dewey Dezimal-Klassifikation:500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:The development of heart failure is often accompanied with cardiac lipid accumulation and inflammation which have been linked to a progressive decline in cardiac function. However, whether cardiac lipid accumulation leads to immune cell-mediated cardiac inflammation is not fully known. Thus, the aim of this work was to study the interaction of heart failure, cardiac lipid deposition and inflammation in a mouse model of pressure overloaded heart. In addition, changes in adipose tissue under chronic cardiac stress conditions should be analyzed.
Cardiomyocyte-specific knock-out of p38 MAPKα (iCMp38KO) was generated in adult mice by tamoxifen injection. Adipose tissue lipolysis was pharmacologically inhibited by atglistatin (anti-lipolytic compound, 0.4 mg/g food), starting from two days prior to pressure overload induction. Pressure overload was induced by angiotensin II (AngII) infusion (1.5 mg/kg/day) for 48 hours via mini-osmotic pumps which were implanted subcutaneously. Echocardiographic analysis of cardiac function was performed using Vevo 2100 imaging system. Hearts were harvested and analyzed for immune cell contents via FACS and histological staining. Transcriptional analysis of heart and adipose tissue was performed by Agilent 8x60K Mouse Array and RT-PCR.
iCMp38KO developed pressure overload-induced heart failure after 48h of AngII administration, with a low ejection fraction (20.5 ± 4.9%) compared to the AngII-treated controls (52.8 ± 7.3%). Pressure overload stress in the AngII-treated iCMp38KO induced lipolysis as indicated by the three-fold increase in circulating glycerol (0.22 ± 0.04 mM) from control level (0.07 ± 0.04 mM). Atglistatin, a small molecule inhibitor of adipose triglyceride lipase (ATGL) was used to inhibit adipose lipolysis. Stress-induced glycerol release in the atglistatin-treated iCMp38KO was lowered by 2-fold. Lipid accumulation was higher in the pressure overloaded iCMp38KO heart (9.96 ± 4.98 pixel2) in contrast to the control heart (0.20 ± 0.09 pixel2). Atglistatin significantly reduced lipid accumulation in iCMp38KO heart by 8-fold. FACS analysis of the cardiac immune cell showed a higher number of neutrophils in iCMp38KO heart (1471 ± 140 cells/mg tissue) compared to the control heart (323 ± 189 cells/mg tissue). Atglistatin treatment led to a reduction in the number of cardiac neutrophils in the iCMp38KO (1059 ± 97 cells/mg tissue). The number of infiltrating macrophages, T cells and B cells tended to be lower in the cardiac tissue of atglistatin-treated iCMp38KO. Left ventricular ejection fraction of the KO was significantly improved to 26.9 ± 5.1% (unpaired Student’s t-test, p < 0.01) with atglistatin treatment, possibly due to significant improvement in fractional shortening. Transcriptional analysis of perigonadal white adipose tissue revealed alterations consistent with an induction of browning, immune cell migration and proliferation, and tissue inflammation in atglistatin-treated iCMp38KO, suggesting an additional role of ATGL which is not restricted to lipolysis.
This study demonstrates that inhibition of adipose tissue lipolysis is a novel approach to reduce cardiac lipid accumulation and to modulate cardiac infiltration of immune cells. Therefore, the iCMp38KO model of pressure overload-induced HF offers the opportunity to study the impact of lipolysis on HF and to evaluate novel therapeutic approach.
Lizenz:In Copyright
Fachbereich / Einrichtung:Medizinische Fakultät » Institute » Institut für Herz- und Kreislaufphysiologie
Dokument erstellt am:12.02.2020
Dateien geändert am:12.02.2020
Promotionsantrag am:04.12.2019
Datum der Promotion:04.02.2020
Status: Gast