Publications by authors named "Gerard Pasterkamp"
Local haemodynamics control arterial homeostasis and dysfunction by generating wall shear stress (WSS) which regulates endothelial cell (EC) physiology. Here we use a zebrafish model to identify genes that regulate EC proliferation in response to flow. Suppression of blood flow in zebrafish embryos (by targeting cardiac troponin) reduced EC proliferation in the intersegmental vessels (ISVs) compared to controls exposed to flow.
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- Genome-wide association studies have found numerous genetic loci linked to glycemic traits, but connecting these loci to specific genes and biological pathways remains a challenge.
- Researchers conducted meta-analyses of exome-array studies across four glycemic traits, analyzing data from over 144,000 participants, which led to the identification of coding variant associations in more than 60 genes.
- The study revealed significant pathways related to insulin secretion, zinc transport, and fatty acid metabolism, enhancing understanding of glycemic regulation and making data available for further research.
Aims: Cellular communication network factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis.
Methods And Results: Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidaemic conditions.
Article Synopsis
- Tobacco smoking increases the risk of atherosclerotic disease, particularly in women, leading researchers to investigate how gene expression in plaques differs between smokers and non-smokers based on sex.
- Analyzing gene expression in 625 carotid plaques revealed that the CRLF1 gene was significantly upregulated in smokers, especially in females, indicating a sex-specific response to smoking.
- The findings suggest that CRLF1, linked to smooth muscle cells and extracellular matrix, may contribute to the heightened cardiovascular risk in female smokers compared to their male counterparts.
Background: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163 macrophages.
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- Atherosclerotic plaques' destabilization is linked to the presence of specific microvessels, which might be leaky, although evidence is still needed.
- This study aimed to find key molecular drivers of dysfunction in these vessels by analyzing transcriptome data from human atherosclerotic lesions and identifying crucial genes related to microvascular density and inflammation.
- The research highlighted Spectrin Beta Non-Erythrocytic 1 (sptbn1) as a central gene that, when silenced, increased vascular permeability and inflammation, suggesting it plays a significant role in regulating the leaky characteristics of plaque microvessels related to cardiovascular disease.
Purpose Of Review: Fatty acid-binding protein 4 (FABP4) plays a role in lipid metabolism and cardiovascular health. In this paper, we cover FABP4 biology, its implications in atherosclerosis from observational studies, genetic factors affecting FABP4 serum levels, and ongoing drug development to target FABP4 and offer insights into future FABP4 research.
Recent Findings: FABP4 impacts cells through JAK2/STAT2 and c-kit pathways, increasing inflammatory and adhesion-related proteins.
Article Synopsis
- Thromboembolic events from advanced atherosclerosis are the main cause of death globally, and lowering lipids through diet and medication is crucial to reduce cardiovascular risks like heart attacks and strokes.
- Researchers fed mice a high-cholesterol diet followed by a zero-cholesterol diet to study the effects of IL-1β treatment on atherosclerotic lesions, using advanced techniques for analysis.
- While lowering lipids improved several health indicators in mice, IL-1β treatment unexpectedly worsened plaque conditions and increased lesion size, indicating a potential risk with this therapy after diet changes.
Article Synopsis
- The study investigates the gene expression changes in vascular cells during atherosclerosis progression, emphasizing the limited understanding of their clinical significance.
- It utilizes single-cell RNA sequencing data from both mouse models and human tissue to identify various cell subtypes involved in advanced atherosclerosis and symptomatic carotid plaques.
- The findings highlight the association of specific gene-regulatory networks with coronary artery disease severity, suggesting pathways that may be targeted for therapeutic strategies.
Article Synopsis
- Epigenetic age acceleration (EAA) in atherosclerotic plaques is linked to future cardiovascular events, showing that older plaque age can predict mortality risk similar to overall epigenetic age estimators.
- In a study involving 485 human carotid plaques, EAA was correlated with clinical indicators, with patients showing higher EAA having conditions like diabetes and obesity.
- Single-cell RNA sequencing identified smooth muscle and endothelial cells as key contributors to plaque EAA, with the endothelial-to-mesenchymal transition process being linked to accelerated aging in those cells.
Article Synopsis
- Some heart disease risk factors can change how a type of blood cell called monocytes reacts to infections.
- Researchers studied these cells from patients with heart disease and found that higher blood pressure makes monocytes less responsive to infection signals.
- A potential new drug, MW-STK33-97, might help improve how these cells react when faced with infections in patients with high blood pressure.
Background: Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects.
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- Histopathological studies of atherosclerotic plaques reveal that diverse lesion types necessitate improved classification methods to understand their clinical significance.
- An analysis of gene expression in 654 human carotid plaques identified five main plaque types, each linked to specific clinical outcomes and differences in cell composition.
- Findings suggest that a particular plaque type with severe symptoms is associated with inflammatory and fibrotic cells, and ongoing research is exploring potential biomarkers for distinguishing these plaque phenotypes.
Article Synopsis
- Myofibroblasts in atherosclerotic plaques play a vital role in disease progression by producing extracellular matrix and contributing to the structure of plaques, yet smooth muscle cells are often used for research instead.
- The study introduces a new method to isolate and culture plaque myofibroblasts from 27 donors, which maintain their growth and retain characteristics of their original cellular environment.
- This research confirms that cultured myofibroblasts closely resemble those found in plaques and can be used effectively in studies examining various mechanisms of atherosclerosis.
Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions.
Arterioscler Thromb Vasc Biol
December 2023
Background: Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model.
Methods: Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3'UTR of the X-linked (biglycan) gene, a proteoglycan highly expressed by SMCs.
Article Synopsis
- Thromboembolic events from advanced atherosclerosis are a major global health issue, and aggressive lipid lowering through diet and drugs is essential to prevent cardiovascular events like heart attacks and strokes.
- A study was conducted using mice to evaluate the impact of switching from a high-fat diet to a low-fat diet on atherosclerotic lesions, involving advanced techniques to analyze lesion characteristics and stability.
- While switching to a low-fat diet significantly lowered LDL cholesterol and improved some aspects of plaque conditions, the addition of an IL-1β antibody treatment unexpectedly worsened the condition by increasing plaque size and cholesterol accumulation.
Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant -differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects.
View Article and Find Full Text PDFThe accumulation of erythrocytes quantified and visualized by Glycophorin C in carotid atherosclerotic plaque reflects intraplaque hemorrhage and pre-procedural neurological symptoms.
Sci Rep
October 2023
Article Synopsis
- The study investigates the role of erythrocyte membranes, specifically through the marker glycophorin C, in atherosclerotic plaques and how they may relate to plaque vulnerability and intraplaque hemorrhage (IPH).
- Researchers analyzed samples from a large cohort of patients who underwent carotid endarterectomy, assessing various plaque features and the prevalence of IPH and neurological symptoms.
- It was found that higher glycophorin C levels were associated with IPH and pre-procedural neurological symptoms, particularly in men, suggesting that these markers could help predict plaque instability.
Article Synopsis
- * Researchers identified over 40 candidate genes related to sex differences in cardiovascular health, focusing on mechanisms impacting vascular remodeling and lipid metabolism, particularly in smooth muscle cells in women.
- * To better understand these sex differences in CAD, the study emphasizes the need for improved research designs that include more women and conduct thorough analysis stratified by sex, alongside integrating various types of biological data.
Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population.
View Article and Find Full Text PDFBackground: Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
Methods: Two hundred nineteen carotid endarterectomy samples were procured from 120 patients. A sequential protein extraction protocol was employed in conjunction with multiplexed, discovery proteomics.
Article Synopsis
- * The study utilized RNA sequencing data to create gene regulatory networks, revealing two main SMC phenotypes in women: a vulnerable myofibroblast-like network and a contractile network, which differed in expression levels compared to males.
- * Findings suggest that female atherosclerosis involves specific gene networks that promote plaque vulnerability, with important implications for understanding disease progression and potential treatment strategies.
Article Synopsis
- - The study explores sex differences in atherosclerosis, particularly focusing on X chromosome inactivation (XCI) skewing in women's atherosclerotic plaques and its potential impact on cardiovascular health and risk factors.
- - Analyzing 154 plaques and 55 blood samples, they found XCI skewing present in about half of the plaques, with no correlation to clinical risk factors but a significant association with plaque hemorrhage.
- - Importantly, while skewed plaques didn't predict major cardiovascular incidents overall, they were linked to an increased risk of peripheral artery events within three years following surgical intervention.