Other Publications (13)
- Thrombosis and Haemostasis
- Clinical Journal of the American Society of Nephrology : CJASN
- European Journal of Heart Failure
- Journal of Intensive Care
- Journal of Biological Methods
- Free Radical Research
- Scientific Reports
- Journal of Critical Care
- International Journal of Molecular Sciences
- Nitric Oxide : Biology and Chemistry
- Advances in Experimental Medicine and Biology
- Journal of Clinical Medicine
Articles by Ulrike B. Hendgen-Cotta in JoVE
Real-time Pressure-volume Analysis of Acute Myocardial Infarction in Mice Lars Michel1, Pia Stock1, Christos Rammos1, Matthias Totzeck1, Tienush Rassaf1, Ulrike B. Hendgen-Cotta1 1West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Medical Faculty, University Hospital Essen Acute myocardial infarction in mice induces acute but incompletely characterized changes in left ventricular (LV) function. LV catheterization in mice undergoing coronary artery occlusion serves as a novel method for a real-time evaluation of LV function.
Other articles by Ulrike B. Hendgen-Cotta on PubMed
Targeted Intracellular Accumulation of Macrophage Migration Inhibitory Factor in the Reperfused Heart Mediates Cardioprotection Thrombosis and Haemostasis. Jan, 2016 | Pubmed ID: 26310191 S-nitrosation of macrophage migration inhibitory factor (MIF) has been shown to be cytoprotective in myocardial ischaemia/reperfusion (I/R) injury. Since the exact mechanism of action is unknown, we here characterise the cardioprotective effects of targeted intracellular accumulation of MIF in myocardial I/R injury. We used different in vivo, ex vivo and in vitro models of myocardial I/R and hypoxia/reoxygenation (H/R) injury to determine MIF levels by immunoblots and ELISA in different phases of reperfusion and reoxygenation, respectively. We discovered a rapid decrease of cardiac MIF that was specific to the early phase of reperfusion. Posttranslational modification of MIF via S-nitrosation--proofed by a modified version of the Biotin Switch Assay--prevented this rapid decrease, leading to a targeted intracellular accumulation of MIF in the early phase of reperfusion. Intracellular MIF accumulation preserved the intracellular ability of MIF to reduce oxidative stress as shown by hydrogen peroxide and aconitase activity measurements. Infarct size measurements by TTC staining showed an overall enhanced cardioprotective effect of this protein by reduction of reperfusion injury. In summary, we have unravelled a novel mechanism of MIF-mediated cardioprotection. Targeted intracellular accumulation of MIF by S-nitrosation may offer a novel therapeutic approach in the treatment of myocardial I/R-injury.
Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double-Blind, Randomized, Placebo-Controlled Trial Clinical Journal of the American Society of Nephrology : CJASN. Jan, 2016 | Pubmed ID: 26681132 Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow-mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)-rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol-rich bioactive food ingredients on acute and chronic HD-induced vascular dysfunction in ESRD.
Impact of Dietary Nitrate on Age-related Diastolic Dysfunction European Journal of Heart Failure. 06, 2016 | Pubmed ID: 27118445 Diastolic dysfunction is highly prevalent, and ageing is the main contributor due to impairments in active cardiac relaxation, ventriculo-vascular stiffening, and endothelial dysfunction. Nitric oxide (NO) affects cardiovascular functions, and NO bioavailability is critically reduced with ageing. Whether replenishment of NO deficiency with dietary inorganic nitrate would offer a novel approach to reverse age-related cardiovascular alterations was not known.
Renal Replacement Therapy Neutralizes Elevated MIF Levels in Septic Shock Journal of Intensive Care. 2016 | Pubmed ID: 27313864 Macrophage migration inhibitory factor (MIF) is known to amplify the immune response in septic animal models. Few clinical data support this pro-inflammatory role in septic patients. Renal replacement therapy (RRT) as adjuvants in the complex therapy of sepsis has been proposed as a possible approach to eliminate elevated circulating cytokines. Since recent data suggest that MIF can be effectively removed from the circulating blood pool in patients with chronic kidney disease, we here aimed to investigate whether RRT in septic shock can lower plasma levels of this pro-inflammatory cytokine in septic shock patients.
A Practical Approach to Remote Ischemic Preconditioning and Ischemic Preconditioning Against Myocardial Ischemia/reperfusion Injury Journal of Biological Methods. 2016 | Pubmed ID: 28066791 Although urgently needed in clinical practice, a cardioprotective therapeutic approach against myocardial ischemia/ reperfusion injury remains to be established. Remote ischemic preconditioning (rIPC) and ischemic preconditioning (IPC) represent promising tools comprising three entities: the generation of a protective signal, the transfer of the signal to the target organ, and the response to the transferred signal resulting in cardioprotection. However, in light of recent scientific advances, many controversies arise regarding the efficacy of the underlying signaling. We here show methods for the generation of the signaling cascade by rIPC as well as IPC in a mouse model for myocardial ischemia/ reperfusion injury using highly reproducible approaches. This is accomplished by taking advantage of easily applicable preconditioning strategies compatible with the clinical setting. We describe methods for using laser Doppler perfusion imaging to monitor the cessation and recovery of perfusion in real time. The effects of preconditioning on cardiac function can also be assessed using ultrasound or magnetic resonance imaging approaches. On a cellular level, we confirm how tissue injury can be monitored using histological assessment of infarct size in conjunction with immunohistochemistry to assess both aspects in a single specimen. Finally, we outline, how the rIPC-associated signaling can be transferred to the target cell conservation of the signal in the humoral (blood) compartment. This compilation of experimental protocols including a conditioning regimen comparable to the clinical setting should proof useful to both beginners and experts in the field of myocardial infarction, supplying information for the detailed procedures as well as troubleshooting guides.
Inorganic Nitrite Modulates MiRNA Signatures in Acute Myocardial in Vivo Ischemia/reperfusion Free Radical Research. Jan, 2017 | Pubmed ID: 28090786 Acute myocardial infarction is the leading cause of mortality in the industrialized world. While it is essential to attempt an early reperfusion of ischemic myocardial territories, reperfusion itself adds damage to the heart, the ischemia-reperfusion (I/R) injury. Particularly the injury resulting from the very first minutes of reperfusion remains incompletely understood. MicroRNAs (miRNAs) are dynamic regulators in I/R injury. Nitric oxide (•NO) signaling, in turn, interacts with miRNA signaling. Our previous investigations showed that •NO signaling in I/R could be modulated by nitrite. We therefore sought to investigate the role of miRNAs in nitrite cardioprotection with focus on the first few minutes of reperfusion. The study was conducted in mice in vivo with 30 min of ischemia and 5 min of reperfusion. Mice received a single-dose of nitrite or saline intracardially 5 min prior to reperfusion. We identified nine miRNAs to be up-regulated after 5 min of reperfusion. The up-regulation of almost half of those miRNAs (miR-125a-5p, miR-146b, miR-339-3p, miR-433) was inhibited by nitrite treatment, perpetuating baseline values. In silico analysis revealed the Irak-M gene to be a target of miR-146b and miR-339-3p. Correspondingly, a rise in Irak-M transcript and protein levels occurred by nitrite treatment within the early phase of reperfusion. The results demonstrate that already a very short phase of reperfusion is sufficient for significant dysregulation in cardiac miRNAs expression and that nitrite preserves baseline values of miRNAs in the scale of only a few minutes. These findings hint at a potential novel cardioprotective mechanism of nitrite signaling.
A Novel Physiological Role for Cardiac Myoglobin in Lipid Metabolism Scientific Reports. Feb, 2017 | Pubmed ID: 28230173 Continuous contractile activity of the heart is essential and the required energy is mostly provided by fatty acid (FA) oxidation. Myocardial lipid accumulation can lead to pathological responses, however the underlying mechanisms remain elusive. The role of myoglobin in dioxygen binding in cardiomyocytes and oxidative skeletal muscle has widely been appreciated. Our recent work established myoglobin as a protector of cardiac function in hypoxia and disease states. We here unravel a novel role of cardiac myoglobin in governing FA metabolism to ensure the physiological energy production through β-oxidation, preventing myocardial lipid accumulation and preserving cardiac functions. In vivoH magnetic resonance spectroscopy unveils a 3-fold higher deposition of lipids in mouse hearts lacking myoglobin, which was associated with depressed cardiac function compared to wild-type hearts as assessed by echocardiography. Mass spectrometry reveals a marked increase in tissue triglycerides with preferential incorporation of palmitic and oleic acids. Phospholipid levels as well as the metabolome, transcriptome and proteome related to FA metabolism tend to be unaffected by myoglobin ablation. Our results reveal a physiological role of myoglobin in FA metabolism with the lipid accumulation-suppressing effects of myoglobin preventing cardiac lipotoxicity.
Elevated MIF-2 Levels Predict Mortality in Critically Ill Patients Journal of Critical Care. 08, 2017 | Pubmed ID: 28329734 D-dopachrome tautomerase (MIF-2 or DDT) is a member of the macrophage migration inhibitory factor (MIF) superfamily and a close structural homolog to MIF. Circulating MIF-2 has been described to be elevated in patients suffering from sepsis, severe burn injury and after surgery. We sought to evaluate the prognostic value of MIF-2 in critically ill patients.
Cytosolic BNIP3 Dimer Interacts with Mitochondrial BAX Forming Heterodimers in the Mitochondrial Outer Membrane Under Basal Conditions International Journal of Molecular Sciences. Mar, 2017 | Pubmed ID: 28333095 The primary function of mitochondria is energy production, a task of particular importance especially for cells with a high energy demand like cardiomyocytes. The B-cell lymphoma (BCL-2) family member BCL-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is linked to mitochondrial targeting after homodimerization, where it functions in inner membrane depolarization and permeabilization of the mitochondrial outer membrane (MOM) mediating cell death. We investigated the basal distribution of cardiac BNIP3 in vivo and its physical interaction with the pro-death protein BCL2 associated X, apoptosis regulator (BAX) and with mitochondria using immunoblot analysis, co-immunoprecipitation, and continuous wave and pulsed electron paramagnetic resonance spectroscopy techniques. We found that BNIP3 is present as a dimer in the cytosol and in the outer membrane of cardiac mitochondria under basal conditions. It forms disulfide-bridged, but mainly non-covalent dimers in the cytosol. Heterodimers with BAX are formed exclusively in the MOM. Furthermore, our results suggest that BNIP3 interacts with the MOM directly via mitochondrial BAX. However, the physical interactions with BAX and the MOM did not affect the membrane potential and cell viability. These findings suggest that another stimulus other than the mere existence of the BNIP3/BAX dimer in the MOM is required to promote BNIP3 cell-death activity; this could be a potential disturbance of the BNIP3 distribution homeostasis, namely in the direction of the mitochondria.
S-nitrosation of Calpains is Associated with Cardioprotection in Myocardial I/R Injury Nitric Oxide : Biology and Chemistry. Jul, 2017 | Pubmed ID: 28392447 Myocardial infarction remains the single leading cause of death worldwide. Upon reperfusion of occluded arteries, deleterious cellular mediators particularly located at the mitochondria level can be activated, thus limiting the outcome in patients. This may lead to the so-called ischemia/reperfusion (I/R) injury. Calpains are cysteine proteases and mediators of caspase-independent cell death. Recently, they have emerged as central transmitters of cellular injury in several cardiac pathologies e.g. hypertrophy and acute I/R injury.
Nitrite-Nitric Oxide Signaling and Cardioprotection Advances in Experimental Medicine and Biology. 2017 | Pubmed ID: 28551796 Cardioprotective strategies to prevent damage to mitochondria in acute myocardial infarction are warranted to reduce lethal myocardial ischemia/reperfusion (I/R) injury. Mitochondrial antagonists in I/R are reactive oxygen species (ROS), deteriorated calcium signaling, permeabilization of the mitochondrial outer membrane (MOM) and deranged mitochondrial structural dynamism (fusion and fission). Nitric oxide (NO) related signaling can protect hearts from I/R. Albeit the underlying signaling is incompletely resolved, recent data point to a particular involvement of protective posttranslational modification of mitochondrial elements. We and others have demonstrated that hypoxic NO signaling in cardiomyocytes is associated with a posttranslational mitochondrial complex I modification to reduce the burden of ROS. Induction of cardioprotective NO signaling may occur through several pathways. These include (i) the supplementation with mitochondria unspecific and specific NO-donors, (ii) the administration of the 'hypoxic-NO donors nitrate and nitrite' and (iii) the enhancement of endogenous NO formation, e.g. by remote ischemic preconditioning maneuvers (rIPC). In this chapter, we outline how NO signaling is activated in the cardiomyocyte, characterize the downstream signaling pathways and discuss how this could translate into a tractable therapeutic approach in patients requiring cardioprotection.
Myocardial Expression of Macrophage Migration Inhibitory Factor in Patients with Heart Failure Journal of Clinical Medicine. Oct, 2017 | Pubmed ID: 29027966 Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory protein and contributes to several different inflammatory and ischemic/hypoxic diseases. MIF was shown to be cardioprotective in experimental myocardial ischemia/reperfusion injury and its expression is regulated by the transcription factor hypoxia-inducible factor (HIF)-1α. We here report on MIF expression in the failing human heart and assess myocardial MIF in different types of cardiomyopathy. Myocardial tissue samples from = 30 patients were analyzed by quantitative Real-Time PCR. MIF and HIF-1α mRNA expression was analyzed in myocardial samples from patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM) and from patients after heart transplantation (HTX). MIF expression was elevated in myocardial samples from patients with ICM compared to NICM. Transplanted hearts showed lower MIF levels compared to hearts from patients with ICM. Expression of HIF-1α was analyzed and was shown to be significantly increased in ICM patients compared to patients with NICM. MIF and HIF-1α mRNA is expressed in the human heart. MIF and HIF-1α expression depends on the underlying type of cardiomyopathy. Patients with ICM show increased myocardial MIF and HIF-1α expression.
Mouse Cardiac Mitochondria Do Not Separate in Subsarcolemmal and Interfibrillar Subpopulations Mitochondrion. Jan, 2018 | Pubmed ID: 28716666 Cardiomyocytes consist of longitudinally oriented myofibril bundles with a misaligned composition caused by the uneven contours of the intercalated discs. The cytoplasmic space harbors the organelles, including mitochondria. This study investigated whether cardiomyocytes contain spatially and ultrastructurally discrete pools of mitochondria that can be separated for structurally and functionally appraisal in (patho)physiology. Transmission electron microscopy disclosed continuous transitions of mitochondria without attributable characteristics from beneath the sarcolemma directly into the barrier-free cytoplasmic space between myofibrils. The various shapes and sizes of mitochondria are formed by myofibril positioning and the space available independent of their localization within the cardiomyocytes. Furthermore, the established enzymatic isolation procedure including proteinase treatment resulted in loss of mitochondrial proteins, as evidenced by immunogold labeling of Connexin43 in situ, a postulated marker for distinguishing mitochondrial subpopulations. Moreover, mitochondrial ATP produced in those mitochondria was not different. These findings preclude a spatial and ultrastructural grading of cardiac mitochondria and their distinct separation and classification in subsarcolemmal and interfibrillar subpopulations.