Gerard Pasterkamp (Netherlands)

University medical center Untrecht Central Diagnostics Laboratory
Gerard Pasterkamp, MD, is Professor of Experimental Cardiology and his research is embedded in the laboratory of clinical chemistry, UMC Utrecht, the Netherlands. The laboratory houses researchers and technicians that cover a broad range of activities. His research interests are in the field of cardiovascular biology and more specifically innovation in biomarkers and drug targets. The research group houses the largest atherosclerotic plaque biobank worldwide: Athero-Express including >4000 patients This biobank has generated new insights into determinants of plaque destabilisation. For example, it has been demonstrated that local plaque characteristics are strongly associated with long term outcome but also that plaque characteristics have rapidly changed in the last decade. The laboratory now invests in the excavation of genetic determinants of atherosclerotic plaque characteristics. Recent insights in the mechanisms of atherosclerosis progression have been obtained by executing whole genome SNP analyses and plaque DNA methylation as well as bulk and single cell sequencing of human atherosclerotic lesions. He coordinates national and EU based consortia and In 2018 he obtained a LeDucq grant together with Prof G Owens (Virginia University) on the role of smooth muscle cell plasticity in the atherosclerotic plaque.

Author Of 3 Presentations

New Phenotypes for Stratification and Modeling of Atherosclerosis (ID 1320)

Session Type
Plenary Session
Session Time
09:30 - 11:03
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
09:33 - 09:53

O008 - Proprotein Convertase Subtilisin/Kexin 6 is involved in lipid metabolism in liver and adipose tissue (ID 706)

Session Type
Lipoproteins and Metabolism
Session Time
11:30 - 13:00
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
12:11 - 12:19

Abstract

Background and Aims

PCSK6 is a protease strongly enriched in human liver however its function in liver has not been fully explored. Here, we aim to investigate the role of PCSK6 in lipid metabolism, and particularly in the context of atherosclerosis.

Methods

We used publically available datasets as well as biobanks to investigate the expression of PCSK6 in healthy and diseased tissues. In addition, we used Pcsk6-/- to investigate the effect of PCSK6 ablation.

Results

Genetic analyses of the PCSK6 locus identified a variant rs7181043 that was significantly associated with PCSK6 mRNA expression in healthy human adipose tissue, liver and in atherosclerotic plaques. The same variant was associated specifically with plaque fat content and atherosclerotic patient’s plasma LDL levels. In addition, PCSK6 mRNA expression in plaques was positively correlated with total plasma cholesterol and LDL levels in atherosclerotic patients. Further analyses using public scRNAseq data of healthy human livers, revealed that PCSK6 is expressed in hepatocytes and stellate cells. Microarray comparison of the livers from Pcsk6-/- mice and wild-type controls showed that VLDL particle assembly was one of the upregulated processes, in adipose tissue we found an increase in inflammatory infiltration and regulation of T cell mediated immunity. Preliminary in vivo studies showed that Pcsk6-/- mice have higher plasma cholesterol and LPL levels at baseline compared to controls, and lower levels of LDLR in their liver.

Conclusions

Our data suggests that PCSK6 is involved in cholesterol and metabolic control. Further experiments are warranted in order to understand the role of PCSK6 in lipid metabolism.

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O013 - A multivariate analysis identifies genetic loci associated with atherosclerotic plaque composition and cardiovascular disease trajectory (ID 728)

Session Type
Genetics
Session Time
15:00 - 16:30
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
15:41 - 15:49

Abstract

Background and Aims

From cross-sectional studies, we have learned that the composition of atherosclerotic plaques differs between individuals, and this contributes to the inter-individual differences in susceptibility to incident coronary and cerebral events. In pathological studies, the extent and type of atherosclerosis are commonly assessed based on histological plaque characteristics that are linked to plaque rupture and erosion. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases. We investigated the genetics of the plaque through multivariate and integrative genome-wide analyses (GWAS) of individual plaque characteristics.

Methods

We included carotid endarterectomy patients from the Athero-Express Biobank Study (n = 2,124) with high-density imputed data and extensive histochemical plaque phenotyping available. We used slideToolKit to quantify the number of endothelial cells, macrophages and smooth muscle cells (SMCs), and manually assessed the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. We ran GWAS on all traits correcting for age, sex, array used, and genetic ancestry.

Results

We identified 3 loci that significantly associate with CD68+ macrophages and ACTA2+ SMCs, p < 5x10-8. Statistical fine-mapping revealed 9 variants in the 95% credible set and functional annotation linked these to genes associated with malignant neoplasms, circulating cholesterol, and transmembrane proteins, suggesting an effect on cellular proliferation and cholesterol metabolism.

Conclusions

We provide evidence for 3 loci that modulate plaque composition through macrophages and smooth muscle cell plaque proliferation and cell-cell interactions.

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Presenter of 1 Presentation

New Phenotypes for Stratification and Modeling of Atherosclerosis (ID 1320)

Session Type
Plenary Session
Session Time
09:30 - 11:03
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
09:33 - 09:53