Wir beschäftigen uns mit der Erforschung Zelltod-aktivierender Mechanismen sowie dem Lipidmetabolismus im Rahmen kardialer Erkrankungen. Hauptziel ist es, neue molekulare Zielstrukturen innerhalb der die Apoptose/Nekrose vermittelnden Signalwege zu identifizieren und Inhibitoren für die therapeutische Anwendung zu designen.
Our group deals with the investigation of cell death-activating mechanisms and the lipid metabolism in the scope of cardiac diseases. The main goal is to identify new molecular targets within the pro-death signaling pathways and to validate inhibitors for therapeutic application.
The current projects focus on heart damage in reperfusion after myocardial ischemia, after ischemic stroke, and by cancer immunotherapeutic agents. A further focus is the analysis of the dynamic lipid metabolism. In particular, we address mitochondrial morphology, energetics, dysfunction, communication and cell death regulation.
Ischemia/Reperfusion injury results from the first minutes of reperfusion. A key pathologic event in cardiac ischemia/reperfusion injury is mitochondrial perturbation rendering the cardiomyocytes to necrotic or apoptotic cell death. We focus on the signaling pathways, which converge the death signals on mitochondria determining the cardiomyocytes fate.
Continuous contractile activity of the heart is essential and the required energy is mostly provided by fatty acid oxidation. Myocardial lipid accumulation can lead to pathological responses. We focus on the role of cardiac myoglobin in governing fatty acid metabolism to ensure the physiological energy production through β-oxidation and preventing myocardial lipid accumulation spectroscopy.
In cerebral ischemic events, the occurrence of acute myocardial injury is common and associated with increased morbidity and mortality. Stroke in the right hemispheric insular cortex induces activation of the sympathetic nervous system resulting in high circulating cardiac troponin levels reflecting myocardial damage. Whether mitochondrial dysfunction plays a crucial role in stroke induced neurogenic cardiac damage is unknown. We hypothesize that sympathetic input to the heart by excessive norepinephrine release induces damage of cardiac mitochondria, which is a major cause for myocardial injury. We will characterize catecholamine toxicity and identify intracellular molecular pathways of mitochondrial damage that act as a central switch for myocardial damage post-stroke.
Immune checkpoint inhibitors play an increasing role in modern anti-tumor therapy.
The immune system has numerous mechanisms to prevent excessive immune response. After T cells activation, certain inhibitory signal molecules, so-called „checkpoints“, are up-regulated on T cells. Via these “checkpoints” tumor cells are able to override the immune defense which is usually directed against them. Checkpoint inhibitors are capable of inhibiting the inhibitory signaling pathways, reactivate T cells and thus give the immune system the opportunity to attack the tumor. However, activation of the body’s immune response against tumor cells can induce cardiotoxic reactions leading to myocarditis, cardiomyopathy and myocardial fibrosis, as well as acute heart failure.
The aim of the present project is the characterization of immunotherapy-induced changes in the murine heart and identification of possible mechanisms that may lead to cardiac damage.
- Hendgen-Cotta UB, Esfeld S, Coman C, Ahrends R, Klein-Hitpass L, Flögel U, Rassaf T, Totzeck M. A novel phsiological role of cardiac myoglobin in lipid metabolism. Sci Rep. 2017; 7:43219
- Hendgen-Cotta UB, Messiha D, Esfeld S, Deenen R, Rassaf T, Totzeck M. Inorganic nitrite modulates miRNA signatures in acute myocardial in vivo ischemia/reperfusion. Free Radic Res. 2017; 51: 91-102
- Esfeld S, Jastrow H, Rassaf T, Winterhager E, Hendgen-Cotta UB. Distinct separation of cardiac subsarcolemmal and interfibrillar mitochondria: Mission impossible? JWMS 2016; 2, 60
- Ecken S, Angermund S, Rassaf T, Hendgen-Cotta UB. AKT-mediated BNIP3 phosphorylation activates BCL-2 family member BAX. Eur Heart J. 2016;37 Suppl 1, 523
- Pohl J, Papathanasiou M, Heisler M, Stock P, Kelm M, Hendgen-Cotta UB, Rassaf T, Luedike P. Renal replacement therapy neutralizes elevated MIF levels in septic shock. J Intensive Care 2016; 4:39
- Ecken S, Hendgen-Cotta UB, Kelm M, Rassaf T
- BNIP3 drives mitochondrial damage in the early phase of myocardial ischemia/reperfusion. Eur Heart J. 2015; 36, 169
- Hendgen-Cotta UB, Luedike P, Totzeck M, Kropp M, Schicho A, Stock P, Rammos C, Niessen M, Heiss C, Lundberg JO, Weitzberg E, Kelm M, Rassaf T.Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation 2012; 126(16):1983-92