A5015522977- Cardiovascular Function and Risk Factors
- Mitochondrial Function and Pathology
- PI3K/AKT/mTOR signaling in cancer
- Polyamine Metabolism and Applications
- Cardiac electrophysiology and arrhythmias
- Tuberous Sclerosis Complex Research
- Adipose Tissue and Metabolism
- Cardiac Ischemia and Reperfusion
- Diabetes Treatment and Management
- Receptor Mechanisms and Signaling
- Mast cells and histamine
- Cancer, Hypoxia, and Metabolism
- Neuroendocrine regulation and behavior
- Cardiac Imaging and Diagnostics
- Phosphodiesterase function and regulation
- Estrogen and related hormone effects
- Cardiovascular and exercise physiology
- Cardiac Fibrosis and Remodeling
- Endoplasmic Reticulum Stress and Disease
- Stress Responses and Cortisol
- Arsenic contamination and mitigation
- Electron Spin Resonance Studies
- Protein Kinase Regulation and GTPase Signaling
- Pharmacological Effects and Assays
- RNA modifications and cancer
Charité - Universitätsmedizin Berlin
2015-2024
German Centre for Cardiovascular Research
2015-2024
Deutsches Herzzentrum München
2024
Johns Hopkins University
2019-2023
University Hospital Heidelberg
2015-2023
Heidelberg University
2015-2023
Johns Hopkins Hospital
2023
Johns Hopkins Medicine
2021-2022
Berlin Institute of Health at Charité - Universitätsmedizin Berlin
2021
Emory University Hospital
2021
Abstract Background Sodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset atrial arrhythmias, a common co-morbidity with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated chronic treatment dual SGLT-1&2 inhibitor...
Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, identity tumor-borne signals their impact on specific peripheral organ systems, particularly heart, remain mostly unknown.By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel seven "cachexokines", including Bridging integrator 1, Syntaxin 7,...
Rationale: The mTORC1 (mechanistic target of rapamycin complex-1) controls metabolism and protein homeostasis is activated following ischemia reperfusion (IR) injury by ischemic preconditioning (IPC). However, studies vary as to whether this activation beneficial or detrimental, its influence on after IR little reported. A limitation prior investigations their use broad gain/loss function, mostly applied before stress. This can be circumvented regulating one serine (S1365) TSC2 (tuberous...
Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus Hsc70-interacting protein (CHIP) is an important regulator proteostasis in cells, having E3-ligase and chaperone functions often directing damaged towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated turnover markedly post-translationally...
Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy dysfunction increases autophagy. oxidation cysteine-42 is also induced these stressors, which blunts its cardioprotective effects.
Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, myocardial fat; stimulates mitochondrial activity brown white improves CMS,...
Abstract Aim Exercise intolerance is the central symptom in patients with heart failure preserved ejection fraction. In present study, we investigated adrenergic reserve both vivo and cardiomyocytes of a murine cardiometabolic HFpEF model. Methods 12‐week‐old male C57BL/6J mice were fed regular chow (control) or high‐fat diet L‐NAME (HFpEF) for 15 weeks. At 27 weeks, performed (stress) echocardiography exercise testing measured its modulation by nitric oxide reactive oxygen species left...
Arsenic exposure though drinking water is widespread and well associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which iAS induces these effects are largely unknown. Recently, an epidemiological study in American population a low burden of risk factors found that was altered left ventricular geometry. Considering possibility directly cardiac remodeling independently hypertension, we investigated impact environmentally relevant on structure function male...
Intimate partner violence (IPV) is a significant public health concern whose neurological/behavioral sequelae remain to be mechanistically explained. Using mouse model recapitulating an IPV scenario, we evaluated the female brain neuroendocrine alterations produced by reiterated male-to-female violent interaction (RMFVI). RMFVI prompted anxiety-like behavior in mice hippocampus displayed marked neuronal loss and hampered neurogenesis, namely reduced BrdU-DCX-positive nuclei diminished...
Blood glucose is one of the most essential parameters in metabolic research. Yet, accurate blood monitoring mouse models diabetes challenging due to significant stress associated with measurements and variability development among experimental models. This necessitates frequent measurements, which only provide intermittent data may not accurately reflect continuous changes. To address these issues, we have utilized Tecniplast DVC system monitor bedding moisture, enabling detection increased...
Precision-based molecular phenotyping of heart failure must overcome limited access to cardiac tissue. Although epigenetic alterations have been found underlie pathological gene dysregulation, the clinical utility myocardial epigenomics remains narrow owing Therefore, current study determined whether patient plasma confers indirect phenotypic, transcriptional, and/or ex vivo cardiomyocytes mirror failing human myocardium. Neonatal rat ventricular myocytes (NRVMs) and single-origin induced...
Background: Type 2 Diabetes mellitus (T2DM) is a common comorbidity in patients after heart transplantation (HTx) and associated with adverse long-term outcomes. Methods: The retrospective study reported here analyzed the effects of vildagliptin therapy stable post-HTx T2DM compared these control for matched-pairs analysis. A total 30 were included study. Fifteen (mean age 58.6 ± 6.0 years, mean time 4.9 5.3 twelve male three female) group (VG) 15 (CG) 61.2 8.3 7.2 6.6 all male). Results:...
Tuberous sclerosis complex-2 (TSC2) negatively regulates mammalian target of rapamycin complex 1 (mTORC1), and its activity is reduced by protein kinase B (Akt) extracellular response (ERK1/2) phosphorylation to activate mTORC1. Serine 1364 (human) on TSC2 bidirectionally modifies mTORC1 activation pathological growth factors or hemodynamic stress but has no impact resting activity. We now show this modification biases ERK1/2 not Akt-dependent TSC2-mTORC1 activation. Endothelin-1–stimulated...
ABSTRACT Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) suppresses established diet-induced CMS in ovariectomized female male mice. PDE9-I reduces abdominal, hepatic, myocardial fat accumulation, stimulates mitochondrial activity brown white fat, improves CMS, without altering or food intake. PDE9 localizes mitochondria, its...
Introduction Holistic phenotyping of rodent models is increasing, with a growing awareness the 3Rs and fact that specialized experimental setups can also impose artificial restrictions. Activity an important parameter for almost all basic applied research areas involving laboratory animals. Locomotor activity, main form energy expenditure, influences metabolic rate, muscle mass, body weight frequently investigated in disease research. Additionally, it serves as indicator animal welfare...
A patient in his 40s presented to the emergency department with chest pain and diaphoresis, which had also occurred 2 days earlier. He a 20 pack-year history of smoking but no family cardiovascular disease. The patient’s electrocardiogram showed biphasic T waves leads V 3 . What would you do next?
Summary The mammalian target of rapamycin complex 1 (mTORC1) is tightly controlled by tuberous sclerosis complex-2 (TSC2) that regulated phosphorylation from kinases responding to environmental cues. Protein kinase G specifically modifies serine-1365 (S1364, human), and its (or phosphomimetic SE mutant) potently blocks mTORC1 co-activation pathological stress, while a phospho-silenced (SA) mutation does the opposite. Neither alter basal activity. Here we show S1365 exerts biased control over...