A5045922112- RNA Research and Splicing
- Cardiomyopathy and Myosin Studies
- Atherosclerosis and Cardiovascular Diseases
- RNA and protein synthesis mechanisms
- Connective tissue disorders research
- MicroRNA in disease regulation
- Cardiac electrophysiology and arrhythmias
- Circular RNAs in diseases
- Aortic aneurysm repair treatments
- Cardiac Fibrosis and Remodeling
- Ion channel regulation and function
- Signaling Pathways in Disease
- RNA modifications and cancer
- Aortic Disease and Treatment Approaches
- Cancer-related molecular mechanisms research
- Congenital heart defects research
- Cholesterol and Lipid Metabolism
- Cancer-related gene regulation
- Cytokine Signaling Pathways and Interactions
- Cardiovascular Effects of Exercise
- Cell Adhesion Molecules Research
- Genetics and Neurodevelopmental Disorders
- Protein Kinase Regulation and GTPase Signaling
- Immune cells in cancer
- Fatty Acid Research and Health
University of Amsterdam
2012-2024
Amsterdam University Medical Centers
2018-2024
Universitas Gadjah Mada
2022
Amsterdam UMC Location University of Amsterdam
2010-2020
Amsterdam UMC Location Vrije Universiteit Amsterdam
2015-2016
Aarhus University Hospital
2016
Ludwig-Maximilians-Universität München
2016
Lung Institute
2015
Max Delbrück Center
2015
Imperial College London
2015
The myocardium of the failing heart undergoes a number structural alterations, most notably hypertrophy cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosis. Connective tissue growth factor (CTGF) is key molecule process fibrosis therefore seems attractive therapeutic target. Regulation CTGF expression at promoter level has been studied extensively, but it unknown how transcripts are regulated posttranscriptional level. Here we provide several...
RNA-binding motif protein 20 (RBM20) is essential for normal splicing of many cardiac genes, and loss RBM20 causes dilated cardiomyopathy. Given its role in splicing, we hypothesized an important forming circular RNAs (circRNAs), a novel class noncoding RNA molecules.To establish the formation circRNAs heart.Here, performed circRNA profiling on ribosomal depleted from human hearts identified expression thousands circRNAs, with some them regulated disease. Interestingly, 80 to be expressed...
Background: Mutations in RBM20 (RNA-binding motif protein 20) cause a clinically aggressive form of dilated cardiomyopathy, with an increased risk malignant ventricular arrhythmias. is splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and CAMK2D (calcium/calmodulin-dependent kinase II delta). Aberrant TTN thought to be the main determinant RBM20-induced but not likely explain Here, we investigated extent which mutation carriers have arrhythmias explore...
Background— Cathepsin K (catK), a lysosomal cysteine protease, was identified in gene-profiling experiment that compared human early plaques, advanced stable and atherosclerotic plaques containing thrombus, where it highly upregulated plaques. Methods Results— To assess the function of catK atherosclerosis, −/− /apolipoprotein (apo) E mice were generated. At 26 weeks age, plaque area /apoE reduced (41.8%) owing to decrease number lesions as well individual area. This suggests an important...
The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of failure. Signalling via TGFβ-pathway is crucial for this remodelling. Here we tested hypothesis that microRNAs in regulate remodelling process inhibition TGFβ-pathway. We show miRNA-15 family, found be up-regulated multiple species, inhibits targeting TGFBR1 several other genes within pathway directly or indirectly, including p38, SMAD3, SMAD7, endoglin. Inhibition...
Background: Surviving cells in the postinfarction border zone are subjected to intense fluctuations of their microenvironment. Recently, cardiomyocytes have been specifically implicated cardiac regeneration. Here, we defined unique transcriptional and regulatory properties, comprehensively validated new molecular markers, including Nppb , encoding B-type natriuretic peptide, after infarction. Methods: Transgenic reporter mice were used identify -positive myocardial Transcriptome analysis...
Abstract Aims In the heart, splicing factors orchestrate functional properties of cardiomyocytes by regulating alternative multiple genes. Work in embryonic stem cells has shown that factor Quaking (QKI) regulates during cardiomyocyte differentiation. However, relevance and function QKI adult remains unknown. this study, we aim to identify vivo mouse heart. Methods results We generated mice with conditional deletion Cre-Lox system. Mice cardiomyocyte-specific died foetal period (E14.5),...
Abstract Marfan syndrome (MFS) is a connective tissue disorder in which aortic rupture the major cause of death. MFS patients with an diameter below advised limit for prophylactic surgery (<5 cm) may unexpectedly experience dissection or rupture, despite yearly monitoring. Hence, there clear need improved prognostic markers to predict such events. We hypothesize that elastin fragments play causal role calcification MFS, and microcalcification serves as marker disease severity. To address...
Circular RNAs (circRNAs) are a relatively new class of RNA molecules, and knowledge about their biogenesis function is still in its infancy. It was recently shown that alternative splicing underlies the formation circular (circRNA) arising from Titin (TTN) gene. Since main mechanism by which circRNAs formed unclear, we hypothesized splicing, particular exon skipping, major driver circRNA production. We performed sequencing on human mouse hearts, mapped events, overlaid these with expressed...
Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier protective mechanisms SGLT2i Empagliflozin (EMPA) are mediated through reductions in sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, SGLT2. Here, we examined role SGLT2, NHE1 and NO a murine TAC/DOCA model HF. SGLT2 knockout mice showed attenuated systolic dysfunction...
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs used to reduce events; however, this not sufficient for most patients. In aorta smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous senescence observed. Resveratrol known enhance sirtuin-1 activity senescence, which prompted us investigate effectiveness resveratrol...
Rationale: ANP (atrial natriuretic peptide) and BNP (B-type peptide), encoded by the clustered genes Nppa Nppb , are important prognostic, diagnostic, therapeutic proteins in cardiac disease. The spatiotemporal expression pattern stress-induction of tightly regulated, possibly involving their coregulation an evolutionary conserved enhancer cluster. Objective: To explore physiological functions cluster elucidate genomic mechanism underlying Nppa-Nppb vivo. Methods Results: By analyzing...
ABSTRACT Circular RNAs (circRNAs) are a class of non-coding RNA molecules that gaining increasing attention for their roles in various pathophysiological processes. The RNA-binding protein quaking (QKI) has been identified as regulator circRNA formation. In this study, we investigate the role QKI formation circRNAs heart by performing RNA-sequencing on Qki-knockout mice. Loss resulted differential expression 17% adult mouse hearts. Interestingly, majority QKI-regulated (58%) were derived...
Secreted phospholipase A2 group X (sPLA2-X) is one of the most potent enzymes lipolytic enzyme superfamily. Its high catalytic activity toward phosphatidylcholine (PC), major phospholipid cell membranes and low-density lipoproteins (LDL), has implicated sPLA2-X in chronic inflammatory conditions such as atherogenesis. We studied role vitro vivo, by generating sPLA2-X-overexpressing macrophages transgenic macrophage-specific mice. Our results show that expression inhibits macrophage...
With consideration of the central role innate immune system in atherogenesis and mannose-binding lectin (MBL) as an regulator immunity, MBL experimental human atherosclerosis was assessed.With use immunohistochemistry polymerase chain reaction, deposition gene expression MBL-A -C were assessed murine from mice deficient for low-density lipoprotein receptor (LDLR(-/-)) after 10 or 18 weeks high-fat feeding. present produced 10-week-old lesions, whereas minimal feeding absent healthy...
Pathological forms of left ventricular hypertrophy (LVH) often progress to heart failure. Specific transcription factors have been identified that activate the gene program induce pathological LVH. It is likely apart from activating transcriptional inducers LVH, constitutive repressors need be removed during development cardiac hypertrophy. Here, we report presence Krüppel-like factor 15 (KLF15) lost in and this loss precedes progression toward We show transforming growth factor-β-mediated...
Oxysterols (oxidised cholesterol) may play a role in the pathogenesis of CVD. Similar to cholesterol, plant sterols are susceptible oxidation. However, less is known about potential atherogenicity oxidised (oxyphytosterols). In present study, mixture oxyphytosterols was examined by feeding female LDL receptor-deficient (LDLR +/ − ) mice for 35 weeks control diet (atherogenic high-fat diet; n 9), an oxysterol (control diet+0·025 % (w/w) oxysterols; 12) or oxyphytosterol oxyphytosterols; 12)....
MicroRNAs (miRNAs) regulate many aspects of cellular function and their deregulation has been implicated in heart disease. MiRNA-30c is differentially expressed the during progression towards failure vitro studies hint to its importance physiology. As little known about vivo miRNA-30c heart, we generated transgenic mice that specifically overexpress cardiomyocytes. We show these display no abnormalities until 6 weeks age, but subsequently develop a severely dilated cardiomyopathy. Gene...
The paralogous genes Nppa and Nppb are organized in an evolutionary conserved cluster a valuable model to study coregulation regulatory landscape organization during heart development disease. Here, we analyzed the chromatin conformation, epigenetic status enhancer potential of sequences Nppa-Nppb vivo. Our data indicate that is present within 60 kbp domain centered around Nppb. Both promoters several elements interact with each other similar manner different tissues developmental stages....
Rationale: Alternative cleavage and polyadenylation (APA) of mRNA represents a layer gene regulation that to date has remained unexplored in the heart. This phenomenon may be relevant, as positioning poly(A) tail mRNAs influences length 3′-untranslated region (UTR), critical determinant expression. Objective: To investigate whether 3′UTR is regulated by APA human heart this changes failing Methods Results: We used 3′end RNA sequencing (e3′-Seq) directly measure global patterns healthy...
Myocardin (MYOCD) is the founding member of a class transcriptional coactivators that bind serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac development. Insights into molecular functions MYOCD have been obtained from cell culture studies, date, knowledge about vivo roles comes exclusively experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance pathogenic variants. This manifested as...