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Introduction
Publications
Publications (165)
Medical scientists” are postgraduate investigators who are engaged in biomedical research, and either hold a biomedical PhD or are qualified in medicine but do not participate in patient care. Medical scientists constitute ~40% of staff at medical faculties and >90% at nonuniversity medical research institutions in Germany. However, medical scienti...
Background and Purpose
Cannabis stimulates several G‐protein‐coupled‐receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid‐signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid‐sensitive...
Aims
Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signaling in atherosclerosis.
Methods and results
Here, we report that male mice with myeloid-specific Cnr1 def...
Background
Peripherally restricted cannabinoid CB1 receptor antagonists without central side effects hold promise for treating metabolic disorders including diabetes and obesity. In atherosclerosis, the specific effects of peripheral CB1 signaling in vascular endothelial cells (ECs) remain incompletely understood.
Methods and results
Endothelial e...
Background and purpose: GPR55 is activated by the endogenous lipid lysophosphatidylinositol, but also sensitive to cannabinoids and antagonized by cannabidiol. While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of GPR55 herein is poorly understood. Thus, we investigated the role of G...
Background
Age and sex are prominent risk factors for heart failure and determinants of structural and functional changes of the heart. Cardiac fibroblasts (cFB) are beyond their task as extracellular matrix-producing cells further recognized as inflammation-supporting cells. The present study aimed to evaluate the impact of sex and age on the infl...
Aim
Cardiovascular diseases (CVDs) are the leading cause of death globally, claiming an estimated 17.9 million lives each year. A better understanding of the underlying chronic inflammatory disease mechanisms in atherosclerosis might help finding novel treatments and reduce CVD deaths. In particular, the cannabinoid receptor CB1 has been implicated...
The sharing and documentation of cardiovascular research data are essential for efficient use and reuse of data, thereby aiding scientific transparency, accelerating the progress of cardiovascular research and healthcare, and contributing to the reproducibility of research results. However, challenges remain. This position paper, written on behalf...
Autophagy is an evolutionarily conserved mechanism of cell adaptation to metabolic and environmental stress. It mediates the disposal of protein aggregates and dysfunctional organelles, although non-conventional features have recently emerged to broadly extend the pathophysiological relevance of autophagy. In baseline conditions, basal autophagy cr...
Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observe...
Atherosclerotic plaques form in the inner layer of arteries triggering heart attacks and strokes. Although T cells have been detected in atherosclerosis, tolerance dysfunction as a disease driver remains unexplored. Here we examine tolerance checkpoints in atherosclerotic plaques, artery tertiary lymphoid organs and lymph nodes in mice burdened by...
Dissecting the pathways regulating the adaptive immune response in atherosclerosis is of particular therapeutic interest. Here we report that the lipid G-protein-coupled receptor GPR55 is highly expressed by splenic plasma cells (PCs), upregulated in mouse spleens during atherogenesis and human unstable or ruptured compared to stable plaques. Gpr55...
Atherosclerosis is a chronic and multifactorial disease accompanied by an imbalance between resolving and pro-inflammatory lipid mediators. Targeting lipid signaling might offer new therapeutical targets for improving the clinical outcome in cardiovascular disease patients. We considered lysophosphatidylinositol (LPI) and its receptor G protein-cou...
Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multi-organ symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. I...
For most cell culture experiments, it is indispensable that the cells are firmly anchored to culture plates, withstanding rinsing steps that can create shear forces and tolerating temperature changes without detaching. For semi-adherent cells such as the common HEK 293 or PC-12 cells, this could so far be obtained by time-consuming plate pre-coatin...
Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes¹. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventit...
Recent advances in cardiovascular research have led to a more comprehensive understanding of molecular mechanisms of atherosclerosis. It has become apparent that the disease involves three layers of the arterial wall: the intima, the media, and a connective tissue coat termed the adventitia. It is also now appreciated that arteries are surrounded b...
A major goal of methodologies related to large scale gene expression analyses is to initiate comprehensive information on transcript signatures in single cells within the tissue’s anatomy. Until now, this could be achieved in a stepwise experimental approach: (1) identify the majority of transcripts in a single cell (single cell transcriptome); (2)...
Arterial vascular diseases, such as coronary heart disease (CHD) and stroke, remain the leading cause of death worldwide and impose enormous socioeconomic costs. This dilemma could be alleviated by improved vascular prevention and treatment, which requires deeper mechanistic research of atherosclerosis as an underlying pathology to drive the develo...
Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In...
Identifying novel pathways regulating the adaptive immune response in chronic inflammatory diseases such as atherosclerosis is of particular interest in view of developing new therapeutic drugs. Here we report that the lipid receptor GPR55 is highly expressed by splenic B cells and inversely correlates with atheroma plaque size in mice. In human ca...
Identifying novel pathways regulating the adaptive immune response in chronic inflammatory diseases such as atherosclerosis is of particular interest in view of developing new therapeutic drugs. Here we report that the lipid receptor GPR55 is highly expressed by splenic B cells and inversely correlates with atheroma plaque size in mice. In human ca...
The increasing use of single-cell immune profiling and advanced microscopic imaging technologies has deepened our understanding of the cardiac immune system, confirming that the heart contains a broad repertoire of innate and adaptive immune cells. Leucocytes found in the healthy heart participate in essential functions to preserve cardiac homeosta...
For most cell culture experiments, it is indispensable that the cells are firmly anchored to the culture plates, tolerating several rinsing steps, and withstanding shear forces or temperature changes without detaching. For semi-adherent cells such as the very common HEK 293 cells, this could so far be obtained only by time-consuming plate pre-coati...
Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility and coagulation. Recent experimental and clini...
While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55−/− and wildtype (WT) mice were basally characteri...
Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most rel...
The pandemic of Coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-infla...
Background and purpose: While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling.
Methods and results: Global GPR55-/- a...
Monocytes are a heterogeneous cell population of innate immune cells with distinct cell surface markers that help them in carrying out different functions. In humans, there are three well-characterized subsets, namely classical (CD14 ⁺⁺ CD16 ⁻ ), intermediate (CD14 ⁺⁺ CD16 ⁺ ) and non-classical (CD14 ⁺ CD16 ⁺⁺ ) monocytes. There is an emerging focu...
Background
Atherosclerosis is accompanied by an imbalance between resolving and pro-inflammatory lipid mediators. Targeting lipid signaling pathways might offer a new anti-inflammatory therapy for improving the clinical outcome in cardiovascular disease patients. We considered lysophosphatidylinositol (LPI) and its receptor G protein-coupled recept...
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which act by guiding AGO (argonaute) proteins to target RNA transcripts in the RNA-induced silencing complex (RISC). This macromolecular complex includes multiple additional components (e.g., TNRC6A) that allow for interaction with enzymes mediating inhibition of translation...
MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for human disease including atherosclerosis, but whether they can exert posttranslational functions to control cell adaptation and whether such noncanonical features harbor pathophysiological relevance is unknown. Here, we show that miR-126-5p sustains endothe...
Ischemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex however affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular...
Cardiac injury may have multiple causes, including ischaemic, non-ischaemic, autoimmune, and infectious triggers. Independent of the underlying pathophysiology, cardiac tissue damage induces an inflammatory response to initiate repair processes. Immune cells are recruited to the heart to remove dead cardiomyocytes, which is essential for cardiac he...
Background
MicroRNAs are versatile regulators of gene expression with profound implications for cardiovascular diseases and atherosclerosis. Among the most expressed in endothelial cells (ECs), the miR-126 duplex is crucial for angiogenesis and vascular protection, featuring different functional roles and homeostasis of the two strands. In line wit...
The role of nonclassical monocytes (NCMs) in health and disease is emerging, but their location and function within tissues remain poorly explored. Imaging of NCMs has been limited by the lack of an established single NCM marker. Here, we characterize the immune checkpoint molecule PD-L1 (CD274) as an unequivocal marker for tracking NCMs in circula...
Background:
ST-segment elevation myocardial infarction (STEMI) displays circadian variability with the highest incidence in the morning hours. Data on whether the time-of-day at symptom onset affects infarct size or patients' long-term prognosis are conflicting. We sought to investigate the association of time-of-day at symptom onset with infarct...
The outcomes of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial have unequivocally proven that inflammation is a key driver of atherosclerosis and that targeting inflammation, in this case by using an anti-interleukin-1β antibody, improves cardiovascular disease (CVD) outcomes. This is especially true for CVD patients with...
Inflammation not only plays a crucial role in acute ischemic cardiac injury, but also contributes to post-infarction repair and remodeling. Traditionally, neutrophils have been merely considered as detrimental in the setting of an acute myocardial infarction. However, recently published studies demonstrated that neutrophils might also play an impor...
Apolipoprotein-E (ApoE) has been implicated in Alzheimer’s disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP)....
In the version of this article originally published, a sentence was erroneously included in the author contributions, and information regarding second shared authorship was missing from the author contributions. The following should not have been included in the author contributions: “C.W. and A.J.R.H. supervised the work presented in Figs. 1, 2, 5...
Endocannabinoids are a group of arachidonic acid-derived lipid mediators binding to cannabinoid receptors CB1 and CB2. An overactivity of the endocannabinoid system plays a pathophysiological role in the development of visceral obesity and insulin resistance. Moreover, elevated circulating endocannabinoid levels are also prevalent in atherosclerosi...
Dysregulated lipid metabolism induces an inflammatory and immune response leading to atherosclerosis. Conversely, inflammation may alter lipid metabolism. Recent treatment strategies in secondary prevention of atherosclerosis support beneficial effects of both anti-inflammatory and lipid-lowering therapies beyond current targets. There is a controv...
Aims:
Myocardial infarction leads to an enhanced release of endocannabinoids and a massive accumulation of neutrophils and monocytes within the ischemic myocardium. These myeloid cells originate from hematopoietic precursors in the bone marrow and are rapidly mobilized in response to myocardial infarction. We aimed to determine whether endocannabi...
Objective—
Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N -acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR-α (peroxisome proliferator-activated receptors α) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inf...
Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in r...
Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1β blockade reduces the incidence of cardiovascular events in pat...
Background: The endocannabinoid system plays a pathophysiological role in metabolic and cardiovascular disorders. G protein-coupled receptor (GPR) 55 is a novel cannabinoid receptor expressed by various lymphocyte subsets, in particular γδT cells, innate lymphoid cells and B1 cells. Its role in regulating immune functions and atherosclerosis is unk...
Objective:
Cardiovascular diseases and depression are the leading causes of disability in Western countries. Clinical data on potential cardiovascular effects of serotonin reuptake inhibitors (SSRIs), the most commonly used antidepressant drugs, are controversial. In addition to blocking serotonin reuptake transporter in the brain, SSRIs deplete t...
Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts...
Background:
The pericardial adipose tissue (AT) contains a high density of lymphoid clusters. It is unknown whether these clusters play a role in post-myocardial infarction (MI) inflammatory responses and cardiac outcome.
Methods:
Lymphoid clusters were examined in epicardial AT of humans with or without coronary artery disease. Murine pericardi...
Objective:
The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transpor...
Objective:
Circadian regulation of neutrophil homeostasis affects myocardial infarction (MI) healing. It is unknown whether diurnal variations of monocyte counts exist in the heart and whether this affects their cardiac infiltration in response to MI.
Approach and results:
Murine blood and organs were harvested at distinct times of day and analy...
Background:
The melanocortin 1 receptor (MC1-R) is expressed by monocytes and macrophages, where it exerts anti-inflammatory actions on stimulation with its natural ligand α-melanocyte-stimulating hormone. The present study was designed to investigate the specific role of MC1-R in the context of atherosclerosis and possible regulatory pathways of...
Physiological cardiovascular functions show daily diurnal variations, which are synchronized by intrinsic molecular clocks and environment-driven cues. The clinical manifestation of cardiovascular disease also exhibits diurnal variation, with an increased incidence in the early morning. This coincides with circadian oscillations of circulating para...
Traditionally, neutrophils have been acknowledged to be the first immune cells that are recruited to an inflamed tissue and have mainly been considered in the context of acute inflammation. By contrast, their importance during chronic inflammation has been studied in less depth. This Review aims to summarize our current understanding of the roles o...
Aims:
Acute myocardial infarction (MI) is the leading cause of mortality worldwide. Anti-inflammatory strategies to reduce neutrophil-driven acute post-MI injury have been shown to limit acute cardiac tissue damage. On the other hand, whether neutrophils are required for resolving post-MI inflammation and repair is unknown.
Methods and results:...
MicroRNAs (miRNAs) coordinate vascular repair by regulating injury-induced gene expression in vascular smooth muscle cells (SMCs) and promote the transition of SMCs from a contractile to a proliferating phenotype. However, the effect of miRNA expression in SMCs on neointima formation is unclear. Therefore, we studied the role of miRNA biogenesis by...
Objective:
ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in th...
Review Process File
Monocytes as cells of the innate immunity are prominently involved in the development of atherosclerotic lesions. The heterogeneity of blood monocytes has widely been acknowledged by accumulating experimental and clinical data suggesting a differential, subset-specific contribution of the corresponding subpopulations to the pathology of cardiovascu...
Background
Microvesicles are gathering increasing attention as mediators of cell communication and as integral effectors of disease. Platelets present a major source of microvesicles and release these microvesicles either spontaneously or upon activation. Platelet microvesicles (PMVs) retain many features of their parent cells and have been shown t...
Nature Communications 7: Article number: 10521 (2016); Published: 3 February 2016; Updated: 7 June 2016 This Article contains an error in the dose of LNA-target site blocker oligonucleotides that was administered. In the Methods section, under the subheading ‘In vivo target site blocker treatment’ the dose ‘0.
