Project Details
Projekt
Adipose tissue ATGL regulates cardiac energy metabolism in heart failure
Applicant
Professor Dr. Ulrich Kintscher
Subject Area
Cardiology, Angiology
Pharmacology
Pharmacology
Term
from 2019 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 431080330
The development of chronic heart failure is characterized by a persistent over-activation of the sympathetic nervous system resulting in the well described cardiovascular consequences. In parallel, frequent adrenergic stimulation exerts crucial effects on adipose tissue metabolism, including a marked induction of adipose tissue lipolysis. We could recently show that adipose tissue lipolysis mediated by the adipose triglyceride lipase (ATGL) directly affectscardiac function during heart failure development involving fatty acid secretion from adipose tissue and changes of circulating lipids. The inhibition of adipose tissue ATGL activity resulted in an improvement of left ventricular function, and may serve as a new therapeutic target. But, the underlying molecular mechanisms by which adipose tissue ATGL regulates cardiac function are incompletely understood. Based on previous data this project aims to investigate the following mechanisms by which adipose tissue ATGL controls cardiac function in heart failure: (1) changes in cardiac energy substrate and systemic metabolism, (2) cardiac phospholipidome changes and the impact on cardiac mitochondrial function, and (3) regulation of cardiac inflammation and its link to mitochondrial function. To achieve these aims we will studyinducible adipose tissue-specific ATGL-deficient (Atgl-fl/fl-Adipoq-cre/ERT2) mice subjected to two different models of heart failure: transverse aortic constriction and prolonged stimulation with the betaadrenergic agonist isoproterenol. Mice will undergo comprehensivecardiac phenotyping including speckle-tracking echocardiography. To assess (1) cardiac energy metabolism we will perform cardiac PET analysis as well as MS-based metabolomics and lipidomics Analysis from left ventricular tissue samples. To determine (2) the relevance of cardiac mitochondrial function for adipose tissue ATGL´s cardioprotective actions, mitochondrial lipid composition and function will be investigated by MS-based mitochondrial lipidomics in isolatedmitochondria and analysis of mitochondrial respiration using the Seahorse technology in isolated primary cardiomyocytes from our models. Finally, our preliminary data points towards a (3) modification of cardiac inflammatory cell infiltration through adipose tissue ATGL.To further clarify this process we will perform an immune cell phenotyping by flow cytometry analysis of cardiac single cell suspensions in the above mentioned models. Finally, we will link the cardiac inflammatory response to mitochondrial dysfunction by investigating the accumulation of mitochondrial DNA in autolysosomes, and a subsequent activation of TLR-9 signaling in cardiomyocytes. In summary, the present study aims to exactly determine the underlying mechanisms of the cardioprotective Actions of adipose tissue ATGL-inhibition in chronic heart failure. These data will help to develop a new ATGL-based pharmacological approach for the treatment of chronic heart failure.
DFG Programme
Research Grants
International Connection
Austria, USA
