Details der Publikation - Atherothrombosis model by silencing of protein C in APOE*3-Leiden.CETP transgenic mice

Atherothrombosis model by silencing of protein C in APOE*3-Leiden.CETP transgenic mice

Abstract Murine atherosclerosis models are key for investigation of atherosclerosis pathophysiology and drug development. However, they do not feature spontaneous atherothrombosis as a final stage of atherosclerosis. Transgenic mice expressing both the human mutant apolipoprotein E form APOE*3-Leiden and human cholesteryl ester transfer protein (CETP), i.e. APOE*3-Leiden.CETP mice, feature a moderate hyperlipoproteinemia and atherosclerosis phenotype. In contrast to apolipoprotein E deficient (Apoeˉ/ˉ) mice, APOE*3-Leiden.CETP mice respond well to lipid-lowering and anti-atherosclerotic drugs. The aim of the study was to investigate whether silencing of anticoagulant Protein C (Proc) allows APOE*3-Leiden.CETP mice to feature thrombosis as a final stage of atherosclerosis. Female APOE*3-Leiden.CETP mice were fed a Western-type diet to induce advanced atherosclerosis, followed by an injection with a small interfering RNA targeting Proc (siProc). Presence of atherosclerosis and atherothrombosis was determined by histologic analysis of the aortic root. Atherosclerosis severity in the aortic root area of APOE*3-Leiden.CETP mice varied from type “0” (no lesions) to type “V” lesions (advanced and complex lesions). Atherothrombosis following siProc injection was observed for 4 out of 21 APOE*3-Leiden.CETP mice (19% incidence). The atherothrombosis presented as large, organized, fibrin- and leukocyte-rich thrombi on top of advanced (type “V”) atherosclerotic plaques in the aortic root. This atherothrombosis was comparable in appearance and incidence as previously reported for Apoeˉ/ˉ mice with a more severe atherosclerosis (19% incidence). APOE*3-Leiden.CETP mice with modest hyperlipidemia and atherosclerosis can develop atherothrombosis upon transient Proc-silencing. This further extends the use of these mice as a test model for lipid-lowering and anti-atherosclerotic drugs..

Medienart:	E-Artikel

Erscheinungsjahr:	2021
Erschienen:	2021

Enthalten in:	Zur Gesamtaufnahme - volume:52
Enthalten in:	Journal of thrombosis and thrombolysis - 52(2021), 3 vom: 30. Mai, Seite 715-719

Sprache:	Englisch

Beteiligte Personen:	Jongejan, Yvonne K. [VerfasserIn] Eikenboom, Jeroen C. J. [VerfasserIn] Gijbels, Marion J. J. [VerfasserIn] Berbée, Jimmy F. P. [VerfasserIn] van Vlijmen, Bart J. M. [VerfasserIn]

Links:	Volltext [kostenfrei]

BKL:	44.85$jKardiologie$jAngiologie
Themen:	Apolipoprotein E3 Atherosclerosis Mice Protein C Thrombosis

Anmerkungen:	© The Author(s) 2021

doi:	10.1007/s11239-021-02488-2

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	OLC2128346991

Internformat


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520			\|a Abstract Murine atherosclerosis models are key for investigation of atherosclerosis pathophysiology and drug development. However, they do not feature spontaneous atherothrombosis as a final stage of atherosclerosis. Transgenic mice expressing both the human mutant apolipoprotein E form APOE3-Leiden and human cholesteryl ester transfer protein (CETP), i.e. APOE3-Leiden.CETP mice, feature a moderate hyperlipoproteinemia and atherosclerosis phenotype. In contrast to apolipoprotein E deficient (Apoeˉ/ˉ) mice, APOE3-Leiden.CETP mice respond well to lipid-lowering and anti-atherosclerotic drugs. The aim of the study was to investigate whether silencing of anticoagulant Protein C (Proc) allows APOE3-Leiden.CETP mice to feature thrombosis as a final stage of atherosclerosis. Female APOE3-Leiden.CETP mice were fed a Western-type diet to induce advanced atherosclerosis, followed by an injection with a small interfering RNA targeting Proc (siProc). Presence of atherosclerosis and atherothrombosis was determined by histologic analysis of the aortic root. Atherosclerosis severity in the aortic root area of APOE3-Leiden.CETP mice varied from type “0” (no lesions) to type “V” lesions (advanced and complex lesions). Atherothrombosis following siProc injection was observed for 4 out of 21 APOE3-Leiden.CETP mice (19% incidence). The atherothrombosis presented as large, organized, fibrin- and leukocyte-rich thrombi on top of advanced (type “V”) atherosclerotic plaques in the aortic root. This atherothrombosis was comparable in appearance and incidence as previously reported for Apoeˉ/ˉ mice with a more severe atherosclerosis (19% incidence). APOE3-Leiden.CETP mice with modest hyperlipidemia and atherosclerosis can develop atherothrombosis upon transient Proc-silencing. This further extends the use of these mice as a test model for lipid-lowering and anti-atherosclerotic drugs.
650		4	\|a Apolipoprotein E3
650		4	\|a Atherosclerosis
650		4	\|a Mice
650		4	\|a Protein C
650		4	\|a Thrombosis
700	1		\|a Eikenboom, Jeroen C. J. \|4 aut
700	1		\|a Gijbels, Marion J. J. \|4 aut
700	1		\|a Berbée, Jimmy F. P. \|4 aut
700	1		\|a van Vlijmen, Bart J. M. \|4 aut
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Atherothrombosis model by silencing of protein C in APOE*3-Leiden.CETP transgenic mice

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