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Track 3 - Pathogenesis of Atherosclerosis
Session Type
Track 3 - Pathogenesis of Atherosclerosis
Room
Hall 3
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Session Ticket
Pre-Recorded
Session Evaluation
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Transendothelial transport

Session Type
Track 3 - Pathogenesis of Atherosclerosis
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:00 - 10:10

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The HDL synapse: Decoding a complex interaction network of HDL residing proteins and endothelial cell surface receptors

Session Type
Track 3 - Pathogenesis of Atherosclerosis
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:10 - 10:20

Abstract

Background and Aims

HDL is thought to affect human health through signalling events triggered by dynamic molecular interactions with cell surface receptors. Despite its system-wide relevance for human health, the molecular mode of action of HDL signalling is not known in detail. Due to the complexity of this particle we hypothesise that multiple receptors participate in HDL signalling, which together assemble to form a condition- and particle-dependent HDL synapse at the cell surface.

Methods

A newly in-house developed proximity labelling strategy termed LUX-MS enables the characterisation of complex ligand-receptor interactions. Receptors proximal to a cell surface bound ligand are tagged in a light-dependant manner and subsequently identified by mass spectrometry. Using LUX-MS we elucidated the HDL synapse, composed of the cell bound HDL proteome and its surrounding receptors, on an endothelial model system.

Results

We identified several HDL proteins, among these APOA1. Furthermore, we identified the known HDL receptor SCARB1 and other novel potential HDL interactors. A substantial number of these candidates were identified in a LUX-MS experiment directly targeting SCARB1 through an antibody, indicating that we captured the SCARB1 environment in the HDL synapse snapshot on endothelial cells.

Conclusions

We propose a new screening strategy to map the complex HDL interaction network at the cell surface. Our data supports the concept of an HDL synapse and receptor candidates are currently undergoing functional validation to prove their relevance in HDL signalling. These findings could provide the basis for the development of therapeutic modulators targeting new HDL receptors to improve prevention of coronary heart disease.

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Sex hormones therapy differentially modulates HDL function in transgender individuals

Session Type
Track 3 - Pathogenesis of Atherosclerosis
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:20 - 10:30

Abstract

Background and Aims

The main proposed atheroprotective function of HDL lays on their role in promoting macrophage cholesterol efflux. A particular hiatus in our knowledge lies in the effects of sex hormones on this HDL function. The aim has been to evaluate the effects of exogenous sex hormones administration on HDL cholesterol efflux capacity (HDL-CEC) within transpeople.

Methods

12 women underwent transition to men (transmen) by treatment with a mix of testosterone esters or testosterone undecanoateand; 10 men underwent transition to women (transwomen) by treatment with 17β estradiol. HDL-CEC was evaluated by radioisotopic technique. Lipid and hormone levels were measured.

Results

In transmen testosterone increased upon exogenous testosterone supplementation (+ 96%; p <0.001), while LH decreased (-68%; p = 0.05). At baseline a normal lipid profile was found, a feature not modified by testosterone except for the increased TG (+11.76%; p = 0.03). Concerning HDL-CEC, only the aqueous diffusion (AD) process decreased (-8.2%; p = 0.024). In transwomen 17β-estradiol supplementation increased estradiol levels (+245%, p=0.034) and decreased that of LH and testosterone (- 96%, p=0.004 and -97%, p<0.0001). The baseline normal lipid profile was not modified by 17β-estradiol except for the reduction in total cholesterol (-11.1%, p=0.009) and HDL-C (- 19%, p=0.001). Total HDL-CEC decreased (- 11%, p=0.004) with a specific decrement in ABCA1- (-21%, p=0.003) and AD-mediated CEC (-7%, p=0.004) independently of HDL-C impairment.

Conclusions

In transmen testosterone supplementation did not change HDL-C levels and associated to a reduction in AD-mediated HDL-CEC. In transwomen, estrogen led to a significant decrease in HDL-CEC-related function independently of HDL-C changes.

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LDL aggregation

Session Type
Track 3 - Pathogenesis of Atherosclerosis
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:30 - 10:40

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Phenotyping carotid endarterectomy plaques of patients with elevated levels of lipoprotein(a)

Session Type
Track 3 - Pathogenesis of Atherosclerosis
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:40 - 10:50

Abstract

Background and Aims

Elevated lipoprotein(a) [Lp(a)] levels have been demonstrated to be a causal risk factor for the development of cardiovascular disease. While previous studies have shown the atherogenicity of Lp(a) on monocyte activation and migration as well by activation of the vessel wall, the atherosclerotic plaque phenotype of individuals with elevated Lp(a) levels have not been studied up till now.

Methods

Therefore, we measured Lp(a) levels in 1506 subjects of the Athero-Express Biobank located at the University Medical Centre Utrecht, The Netherlands. Athero-Express started in 2002 and is a prospective ongoing biobank study that includes all patients undergoing carotid or iliofemoral endarterectomy in two referral hospitals in the Netherlands. From these 1506 subjects we compared the plaques from patients with extremely high (>195 mg/dl; N=57) and low (<7 mg/dl; N=106) Lp(a) levels.

Results

The plaques from Lp(a) high patients demonstrated a 33% increase in blood vessel area per plaque, indicating an increased plaque angiogenesis. Intraplaque neovascularization has been shown to drive the progression of atherosclerosis and enhance plaque instability leading to an increase in cardiovascular risk.

Conclusions

By using whole plaque RNA sequencing, combined with immunohistochemistry and targeted plasma biomarker analysis by OLINK proteomic panels, we aim to further characterise the plaque phenotype in patients with elevated levels of Lp(a) and thereby provide more insight in the atherogenic potential of Lp(a). Further analyses are currently performed and the results will be available at the EAS 2020.

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Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation

Session Type
Track 3 - Pathogenesis of Atherosclerosis
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:50 - 11:00

Abstract

Background and Aims

Patients with elevated levels of Lp(a) are hallmarked by increased arterial wall inflammation on 18F-FDG PET/CT, which has been shown to predict future cardiovascular risk. The endothelium is the first line of defence against pro-inflammatory changes in the artery wall. Recent evidence suggested that lipids may induce a pro-inflammatory state by altering intracellular metabolic responses. Therefore, we hypothesized that Lp(a) mediates endothelial inflammation via metabolic reprogramming, facilitating a pro-inflammatory environment, thereby driving monocyte migration through the vessel wall.

Methods

RNAseq, Metabolic-Flux-Analysis, TEM, qPCR, atherosclerosis-biobank

Results

In-depth RNA-sequencing of Human Arterial Endothelial Cells (HAECs) stimulated with Lp(a) significantly induced inflammatory pathways involved in efficient leukocyte adhesion and migration. This was confirmed by targeted qPCR, attested by a significant increase in leukocyte adhesion molecules MCP-1, ICAM-1, VCAM-1 (2.9, 5.0 and 3.1-fold increase in gene-expression, respectively) with a concomitant 7.1-fold increase in monocyte transendothelial migration (TEM).This inflammatory endothelial phenotype coincided with increased expression of key glycolytic genes PFKFB3, HK2 and PFKM (2.9, 2.3 and 2.1-fold increase respectively), whereas glycolytic flux analysis corroborated an 85% increase in glycolytic activity. Pharmacological inhibition of inducible glycolysis (PFKFB3) by PFK158 abolished the inflammatory signature and reduced TEM by 75%. These findings were substantianted using a large Atherosclerotic Endarterectomy Biobank (Athero-Express).

Conclusions

This data is the first that shows that Lp(a) activates the endothelium by enhancing inducible-glycolysis, leading to induction of a pro-adhesive state which can be reversed by specific inhibition of inducible-glycolysis. This novel finding paves the way for therapeutic agents targeting metabolic reprogramming to reduce the pro-inflammatory state in cardiovascular-patients.

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