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Carbamylated Lipoproteins: Triggers of Vascular Dysfunction?

English title Carbamylated Lipoproteins: Triggers of Vascular Dysfunction?
Applicant Tanner Felix
Number 135781
Funding scheme Project funding
Research institution Service de Cardiologie Département de Médecine Interne Hôpitaux Universitaires de Genève
Institution of higher education University of Zurich - ZH
Main discipline Cardiovascular Research
Start/End 01.04.2011 - 30.09.2014
Approved amount 149'796.00
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Keywords (6)

Tissue Factor; Thrombosis; Nitric Oxide; Vasospasm; Renal Failure; Lipoprotein Carbamylation

Lay Summary (German)

Lead
Lay summary
Kardiovaskuläre Ereignisse wie Herzinfarkt oder Hirnschlag treten auf, wenn eine Arterie durch ein Gerinnsel verschlossen wird. Patienten mit chronischem Nierenversagen weisen ein sehr hohes Risiko für kardiovaskuläre Ereignisse auf. Bei solchen Patienten werden im Blut zirkulierende Lipoproteine wie LDL und HDL chemisch verändert (Carbamylierung). Es ist aber bisher nicht erforscht worden, ob solche veränderten Lipoproteine die Entstehung von arteriellen Gerinnseln und damit kardiovaskulären Ereignissen begünstigen können. Das vorliegende Projekt wird dieser Frage nachgehen und sowohl künstlich carbamylierte als auch von Patienten isolierte Lipoproteine verwenden. Dabei wird das Projekt auf zwei für die Entstehung von arteriellen Gerinnseln wichtigen Aspekten fokussieren. Erstens wird die Wirkung der Lipoproteine auf den Tissue Factor, das Schlüsseleiweiss zur Auslösung der Blutgerinnung, untersucht. Diese Experimente werden in isolierten menschlichen Zellen durchgeführt. Zweitens wird der Einfluss der Lipoproteine auf den Gefässtonus, welcher die Bildung von Gerinnseln evenfalls beeinflussen kann, studiert. Diese Experimente werden in isolierten Blutgefässen von Mäusen und Patienten durchgeführt. Schliesslich wird das Zusammenwirken dieser Faktoren in der Entstehung von arteriellen Gerinnseln in einem in vivo Modell in der Maus untersucht. Diese Experimente werden mittels zahlreicher Methoden hinsichtlich der Rolle von Tissue Factor sowie anderer Gerinnungsfaktoren, Blutplättchen, und Blutgefässen durchgeführt.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Carbamylated low-density lipoproteins induce a prothrombotic state via LOX-1: impact on arterial thrombus formation in vivo
HolyErik (2016), Carbamylated low-density lipoproteins induce a prothrombotic state via LOX-1: impact on arterial thrombus formation in vivo, in J Am Coll Cardiol, 68(15), 1664-1676.
Carbamylated Low-Density Lipoproteins Induce a Prothrombotic State Via LOX-1: Impact on Arterial Thrombus Formation In Vivo.
Holy E (2016), Carbamylated Low-Density Lipoproteins Induce a Prothrombotic State Via LOX-1: Impact on Arterial Thrombus Formation In Vivo., in J Am Coll Cardiol, 68, 1664-1676.
Carbamylated low-density lipoprotein induces endothelial dysfunction.
Speer T (2014), Carbamylated low-density lipoprotein induces endothelial dysfunction., in Eur Heart J, 35, 3021-3032.
High-density lipoprotein from patients with coronary heart disease loses anti-thrombotic effects on endothelial cells: impact on arterial thrombus formation.
Holy E (2014), High-density lipoprotein from patients with coronary heart disease loses anti-thrombotic effects on endothelial cells: impact on arterial thrombus formation., in Thromb Haemost, 112, 1024-1035.
PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design.
Holy E (2014), PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design., in Eur Heart J, 35, 808-820.

Collaboration

Group / person Country
Types of collaboration
Dr. Dr. Ferdinand H. Bahlmann / Nephrologie Homburg/Saar Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Abstract

Chronic renal failure is associated with a markedly increased incidence of cardiovascular events such as myocardial infarction and cardiac death. Lowering lipoprotein levels does not affect survival of hemodialysis patients, suggesting that lipoprotein modifications rather than plasma levels trigger vasospasm and thrombosis and thereby evoke cardiovascular events in these patients.Carbamylated lipoproteins are non-enzymatically modified lipoproteins circulating at high plasma concentrations in patients with chronic renal failure. A pathogenic role for these lipoproteins in the progression of atherosclerosis is emerging. However, it is not known whether such lipoproteins modulate vascular tone and thrombosis.In preliminary experiments, we observed that carbamylated low-density lipoproteins induce expression of tissue factor, the key trigger of thrombosis, in a potent manner. Moreover, we discovered that these lipoproteins inhibit endothelium-dependent relaxations mediated by nitric oxide, an important mediator of vascular relaxation and antagonist of vasospasm. Therefore, we believe that this project deserves further investigation.We propose to study the effect of carbamylated low-density and high-density lipoproteins obtained a) by modification of native lipoproteins ex vivo and b) by isolation from patients with chronic renal failure. We will first examine whether these lipoproteins alter a) expression and release of mediators regulating vascular tone as well as b) expression and activity of mediators regulating vascular thrombosis. These experiments will be performed in isolated human cells. We will then investigate whether these alterations are relevant for a) the regulation of vascular tone as well as b) the regulation of vascular thrombosis. These experiments will be performed in isolated mouse and human vessels as well as in a mouse model of arterial thrombosis in vivo. In these experiments, particular attention will be paid to the interaction and the relative importance of the different mediators involved in regulating vascular tone and thrombosis.In this innovative project, we will employ cellular models and animal models of cardiovascular disease as well as human cells and human vessels. We will assess whether carbamylated lipoproteins regulate vascular tone and thrombosis. This information will not only be important for our pathophysiological understanding, but also for current clinical treatment, because we will learn whether it is more important to prevent lipoprotein modification rather than lower lipoprotein levels in patients with chronic renal failure. Hence, this project might influence the current treatment options for these patients.
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