Kim E. Dzobo (Netherlands)
Amsterdam UMC Experimental Vascular MedicineAuthor Of 2 Presentations
O022 - Elucidating the atherogenicity of Lp(a): an unbiased lipidomics approach (ID 472)
Abstract
Background and Aims
Mendelian randomisation as well as epidemiology studies have established an association between elevated lipoprotein(a) [Lp(a)] levels and increased cardiovascular risk. Besides the pro-atherogenic properties of the LDL- like moiety, Lp(a) further contributes to the disease pathology by carrying pro-inflammatory oxidized phospholipids (OxPLs). While blocking these OxPL epitopes profoundly reduces the monocytic inflammatory response, a residual inflammatory risk remains.
Methods
To determine the contributing factors resulting in this residual inflammation, we performed lipidomics on complete plasma from healthy individuals with either elevated [median 87 mg/dL (218 nmol/L); N=12]or low [median 7 mg/dL (18 nmol/L); N=13] levels of Lp(a).
Results
Using this unbiased lipidomics approach, we discovered a distinct “lipidome” in individuals with elevated Lp(a) levels as displayed by an upregulation of several diacylglycerol species (DAGs) and lysophosphatic acid (LPA). Further fractionation and purification of different lipoprotein fractions showed that these DAGs are preferentially carried by Lp(a). Next, we functionally assessed if these upregulated DAGs are able to elicit an inflammatory response in monocytes. Upon ex vivo DAG stimulation, monocytes elicited a dose dependent increase in IL-8, IL-6 and IL-1β secretion. Functionally, our preliminary data demonstrated this coincided with increased transendothelial migration.
Conclusions
By using transwell migration assays with fluorescently labelled monocytes, combined with sprouting assays and in-depth phosphorylation analysis, we aim to further characterise the pathways effected by DAGs and LPA to further unravel the atherogenicity of Lp(a) and will be available at the EAS 2021.
O054 - Phenotyping carotid endarterectomy plaques of patients with elevated levels of lipoprotein(a) (ID 481)
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
Analysis showed that plaques from patients with elevated Lp(a) levels 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 increased cardiovascular risk.
Conclusions
So far, we have shown that human arterial endothelial cells stimulated with Lp(a) show enhanced collagen degradation capacity, probably due to increased migratory capacity and matrix metalloproteinase (MMP) activity. By using whole plaque RNA sequencing, combined with immunohistochemistry and ex-vivo validation studies (data available at the EAS 2021), 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).
Presenter of 2 Presentations
O022 - Elucidating the atherogenicity of Lp(a): an unbiased lipidomics approach (ID 472)
Abstract
Background and Aims
Mendelian randomisation as well as epidemiology studies have established an association between elevated lipoprotein(a) [Lp(a)] levels and increased cardiovascular risk. Besides the pro-atherogenic properties of the LDL- like moiety, Lp(a) further contributes to the disease pathology by carrying pro-inflammatory oxidized phospholipids (OxPLs). While blocking these OxPL epitopes profoundly reduces the monocytic inflammatory response, a residual inflammatory risk remains.
Methods
To determine the contributing factors resulting in this residual inflammation, we performed lipidomics on complete plasma from healthy individuals with either elevated [median 87 mg/dL (218 nmol/L); N=12]or low [median 7 mg/dL (18 nmol/L); N=13] levels of Lp(a).
Results
Using this unbiased lipidomics approach, we discovered a distinct “lipidome” in individuals with elevated Lp(a) levels as displayed by an upregulation of several diacylglycerol species (DAGs) and lysophosphatic acid (LPA). Further fractionation and purification of different lipoprotein fractions showed that these DAGs are preferentially carried by Lp(a). Next, we functionally assessed if these upregulated DAGs are able to elicit an inflammatory response in monocytes. Upon ex vivo DAG stimulation, monocytes elicited a dose dependent increase in IL-8, IL-6 and IL-1β secretion. Functionally, our preliminary data demonstrated this coincided with increased transendothelial migration.
Conclusions
By using transwell migration assays with fluorescently labelled monocytes, combined with sprouting assays and in-depth phosphorylation analysis, we aim to further characterise the pathways effected by DAGs and LPA to further unravel the atherogenicity of Lp(a) and will be available at the EAS 2021.
O054 - Phenotyping carotid endarterectomy plaques of patients with elevated levels of lipoprotein(a) (ID 481)
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
Analysis showed that plaques from patients with elevated Lp(a) levels 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 increased cardiovascular risk.
Conclusions
So far, we have shown that human arterial endothelial cells stimulated with Lp(a) show enhanced collagen degradation capacity, probably due to increased migratory capacity and matrix metalloproteinase (MMP) activity. By using whole plaque RNA sequencing, combined with immunohistochemistry and ex-vivo validation studies (data available at the EAS 2021), 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).