Research projects

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1. Morphological-functional correlates of cardiovascular diseases

Principle Investigator: Prof. Ulrich Kintscher 

Investigator: Niklas Beyhoff

The cardiac function is mainly determined by its (intact) structural composition. Nearly all cardiovascular diseases are accompanied by changes of the cardiac microstructure („cardiac remodeling“), which can lead to an impairment of myocardial mechanics. The aim of this project is an improved understanding of these remodeling processes and their impact on myocardial mechanics in order to identify novel diagnostic methods. For this purpose, state-of-the-art imaging methods such as speckle-tracking echocardiography are utilized for further correlations with histological data and biomarkers.

2. Pharmacological Characterization of New Lipid Mediators in Chronic Heart Failure

Principle Investigators: Prof. Ulrich Kintscher
Investigators: Eleya Sameer
Funding: Else Kröner Fresenius Stiftung (EKFS)

Heart failure (HF) is a chronic, debilitating disease that impairs the ability of the heart to respond to increased demands for cardiac output. Recently, lipids have gained increasing interest as biomarkers, molecular mediators and therapeutic agents for various diseases including cardiovascular disease. Major contributors to this development have been new advanced technologies for the analysis of lipid species on a systems level by lipidomic profiling using sensitive mass spectrometry (MS) technologies. In parallel to these clinical/ technical developments, lipid species have been characterized as endogenous molecular mediators of cardiac morphology and function.
In our study we aim to investigate the role of circulating and cardiac lipids in the development of heart failure. For this, we will combine molecular, cellular and in-vivo approaches with state-of-the-art lipidomic profiling. We aim to identify new lipid mediators involved in the pathogenesis of chronic heart failure, and we want to understand how cellular lipids contribute to pathological responses under established cardiac stressors such as catecholamines.

3. C16:1-mediated effects on AKT/mTOR/FOXO signaling in cardiomyocytes

Principle Investigators: Prof. Ulrich Kintscher and PD Anna Foryst-Ludwig
Investigators: Sarah Julia Qaiyumi
Funding: Charité

Our recently publish data indicate that Palmitoleic Acid (C16:1) mediate exercise-induced development of physiological cardiac hypertrophy. While the in vivo cardiac effects of palmitoleic acid have been investigated extensively, the fundamental molecular signaling of this fatty acid in cardiomyocytes remains widely unclear.
The finding that C16:1 promotes the phosphorylation of the AKT protein (Foryst-Ludwig et al.) is currently the only hint to how palmitoleic acid brings about these physiological cardiac growth processes. Therefore the target of this projects is to investigate the impact of C16:1 on the AKT/FOXO signaling pathway, using a variety of different molecular biology techniques, in order to fully grasp the cellular processes that are being triggered by C16:1  and how they ultimately bring out physiological cardiac hypertrophy.

4. The influence of palmitoleic acid on cardiomyocytes and their nuclear hormone receptor expression profile and the impact on cardiac hypertrophy

Principle Investigators: PD Anna Foryst-Ludwig and Prof. Ulrich Kintscher
Investigators: Iris Betz, Sarah Brix
Funding: Charité

This project investigates the impact of palmitoleic acid (C16:1) on nuclear hormone receptors in the heart and especially its role in the development of physiologic hypertrophy. While we already know some of the effects on the heart in vivo the basic molecular signaling pathways of this fatty acid are still widely unknown.
Nuclear hormone receptors are part of a family of transcription factors which are located in cytosol and the nucleus of the cell. Classic ligands are hormones and lipids like e.g. steroids, androgens or vitamin A.
The aim of this project is to learn more about the signaling pathways and the pro-hypertrophic effects of this adipokine using novel sequencing methods. In cooperation with the Helmholtz-Institut Munich (H. Uhlenhaut) we are planning to explore the differential genome expression of C16:1 in cardiomyocytes.
By studying the effects palmitoleic acid on a molecular level we want to provide a new therapeutic option for patients suffering under heart hypertrophy and heart failure in the near future.

5. Effects of Estrogen-receptor alpha and dietary lipids on metabolism and immune response

Principle Investigators: Prof. Ulrich Kintscher, PD Anna Foryst-Ludwig;
Investigators:  Zsofia Ban
Funding: Deutsche Forschungsgemeinschaft (DFG)

Estrogen-receptor alpha is one of the major regulators in metabolism and obesity. In this project we aimed to define the relevance of adipose tissue ERalpha during high-fat diet (HFD)-induced obesity using a tissue specific knock-out model (atERKO). To our surprise HFD did not affect metabolic parameters in atERKO but induced severe inflammation processes.
These infections were characterized by massive uterine neutrophil infiltration and marked reduction of "anti-inflammatory"-macrophages, pointing to an affected immune response. In parallel, this model was linked to high estradiol levels. Therefore, we decided to focus on the interactions between estrogen signaling and dietary lipids, especially in regard to the effects on the immune response. Indeed, we identified stearic acid (C18:0) in a lipid profiling approach, as a fatty acid prominently induced by HFD, which is able to induce ERalpha-acylation. We could show, that this fatty acid inhibits E2-induced transcriptional activity and estradiol-stimulated anti-inflammatory macrophage polarization.
In summary, we are interested in the molecular mechanism, by which dietary fatty acids can influence the function of nuclear hormone receptor such as estrogen receptor alpha.

6. Adipose tissue specific ATGL lipase regulates cardiac lipid metabolism and protects against pressure overload-induced heart failure

Principle Investigators: Prof. Ulrich Kintscher and PD Anna Foryst-Ludwig
Investigators: Janek Salatzki
Funding: DFG

Cardiac metabolism undergoes changes in response to pathological hypertrophy (PH), characterized by increased reliance on glucose and decreased free fatty acid (FFA) oxidation. Also cardiac metabolism is influenced by other organs such as adipose tissue (AT). We aimed to investigate the effect of Adipose Triglyceride Lipase (ATGL) in AT on the development of PH in a pressure overload-induced cardiac hypertrophy model in mice.
In this study, we demonstrate that atATGL is crucial for the development of pressure overload-induced PH. The lack of ATGL in adipose tissue, the associated reduced lipolysis and the subsequent switch in cardiac metabolism from FFA oxidation to glycolysis are potential underlying mechanisms of this process.

7. Effects of a novel nonsteroidal mineralocorticoid receptor antagonist on cardiac hypertrophy

Principle Investigator: Prof. Ulrich Kintscher
Investigators: Jana Grune
Funding: Bayer Pharma AG

Pharmacological blockade of mineralocorticoid receptors (MR) is known as an efficacious therapy in chronic heart failure. In consonance, current steroidal MR-antagonists such as spironolactone and eplerenone have been demonstrated to counteract negative MR actions, and to exhibit broad cardiovascular protective actions. However, current steroidal MR-antagonists are limited due to major side effects such as hyperkalemia, gynecomastia, impotence, erectile dysfunction and menstrual disturbances. Thus, new non-steroidal MR-antagonists with an improved efficacy/ side effect profile are currently developed.
Finerenone is a new non-steroidal MR antagonist developed from the chemical class of dihydropyridines (DHP) with high MR-potency and excellent MR-selectivity. Interestingly, DHP-based MR-antagonists display a distinct MR binding mode compared to steroidal antagonists resulting in an unstable receptor-ligand complex and distinct gene expression. Therefore, we were aiming to characterize the pharmacological actions of the non-steroidal MR-antagonist finerenone on cardiac gene expression, and on cardiac remodeling during pressure overload compared to steroidal MR-antagonists.

8. HDAC6 controls the development and progression of cardiac mal-adaptive hypertrophy

Principle Investigators: PD Anna Foryst-Ludwig and Prof. Ulrich Kintscher
Investigators: Sarah Brix
Funding: Deutsche Stiftung für Herzforschung

HDACs (Histone Deacetylases) have been identified as central regulators of mal-adaptive hypertrophy. Moreover, HDAC6 enzymatic activity is strongly upregulated in different models of pressure-induced cardiac hypertrophy. Given the importance of HDACs - and in particular HDAC6- in the development of mal-adaptive hypertrophy, a HDAC6 specific inhibitor (HDACi) and a general HDACi were investigated in contexts of cardiac hypertrophic response. In vitro we tested the pharmacological effects of both inhibitors on murine HL-1 cardiomyocytes and furthermore to investigate the functional importance of HDAC6 in the development of cardiac hypertrophy we performed an in vivo study. In summary, this study demonstrates for the first time that treatment with the selective HDAC6 inhibitor significantly reduces cardiac hypertrophic responses. HDAC6 specific inhibitors might be promising pharmacological tools to prevent mal-adaptive hypertrophy in the future.



9. Endogenous reprogramming of cardiac fatty acid metabolism to treat diabetic cardiomyopathy

Principle Investigator: Prof. Ulrich Kintscher

Investigators: Daniel Ritter, PD Anna Foryst-Ludwig and Dr. Jana Grune

Funding: German Center for Cardiovascular Research (DZHK)

One of the main causes of death of patients with diabetes mellitus are cardiovascular diseases. Although coronary heart disease is the leading cause of cardiac complications in diabetics, functional and structural changes are observable, even without evidence of coronary heart disease or hypertension. Essential for this are the changes in myocardial energy metabolism, whereby the diabetic heart is relying increasingly on fatty acids instead of glucose as an energy source. Those cardiac structural and functional changes triggered by metabolic dysregulation of the diabetic heart are termed diabetic cardiomyopathy.

Additional pathophysiological mechanisms characterizing the diabetic cardiomyopathy are cardiac insulin resistance, hyperglycemia, cardiac lipid accumulation (lipid toxicity), local inflammation and cardiac fibrosis.

It is known that specific fatty acids can have a cardio protective and anti-inflammatory effect. Therefore, this project is dedicated to investigate the nuclear receptor co-repressor (NCoR) and its potential role on the endogenous cardiac fatty acid metabolism contributing a beneficial effect on the diabetic cardiomyopathy.

The options for the prevention, early diagnosis and treatment of the diabetic cardiomyopathy are limited. Therefore further investigations on the exact pathomechanisms are needed to develop new potential therapeutic approaches.

10. Drosophila melanogaster as a model to study heart function

Principle Investigators: Prof. Ulrich Kintscher and Anna Foryst-Ludwig
Investigators: Annelie Blumrich
Funding: German Center for Cardiovascular Research (DZHK)

The fruit fly Drosophila melanogaster has long been used as a model organism to understand not only basic genetics but also multiple human diseases. The vast array of sophisticated techniques allows researchers to utilize D. melanogaster in a broad range of research fields. Furthermore, researchers benefit from a fast life cycle and easy laboratory handling. Moreover, tissue-specific knockdown (KD) of genes is fast and easy to generate in Drosophila, compared to mammalian systems.
Recently, elegant methods were developed to investigate heart function in D. melanogaster (Ocorr 2014, Methods). We would like to employ these techniques to study interorgan-communication, more specifically the interactions between fat body and heart. Fruit flies have a linear, contractile heart tube that pumps hemolymph into the body. High-speed optical recording and specific movement detection algorithms (Fink 2009, Biotechniques) allow functional analysis of the Drosophila heart tube. This work will be employed in close collaboration with one of the worldwide leading laboratories in the studies of Drosophila heart function: Rolf Bodmer, Sanford-Burnham-Institute San Diego, USA.
Our aim is to identify new lipid mediators regulating Drosophila heart function. Using Drosophila as a model organisms we would like to determine lipid-dependent cardiac signaling pathways and putative target molecules involved in heart disease pathogenesis.