Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic mice
Background: Elevated von Willebrand factor (VWF) levels correlate with higher risk of atherosclerosis-related arterial thrombosis (atherothrombosis). Silencing the VWF gene via small-interfering RNAs (siRNAs) could mitigate this risk. Previous studies successfully delivered siRNA to the endothelium...
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Elsevier
2025-01-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2475037925000238 |
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| author | Yvonne K. Jongejan Richard J. Dirven Elisa Schrader Echeverri Anke J.L. de Jong Amanda C.M. Pronk Sander Kooijman Patrick C.N. Rensen James E. Dahlman Jeroen C.J. Eikenboom Bart J.M. van Vlijmen |
| author_facet | Yvonne K. Jongejan Richard J. Dirven Elisa Schrader Echeverri Anke J.L. de Jong Amanda C.M. Pronk Sander Kooijman Patrick C.N. Rensen James E. Dahlman Jeroen C.J. Eikenboom Bart J.M. van Vlijmen |
| author_sort | Yvonne K. Jongejan |
| collection | DOAJ |
| description | Background: Elevated von Willebrand factor (VWF) levels correlate with higher risk of atherosclerosis-related arterial thrombosis (atherothrombosis). Silencing the VWF gene via small-interfering RNAs (siRNAs) could mitigate this risk. Previous studies successfully delivered siRNA to the endothelium of healthy, wild-type (WT) mice using lipid nanoparticles (LNPs). Objectives: This study aimed to investigate whether the LNP-siRNA strategy could achieve endothelium-specific Vwf-silencing under diseased conditions of prolonged hypercholesterolemia and atherothrombosis-prone vasculature. Methods: Female transgenic mice expressing a variant of human APOE∗3 (ie, APOE∗3-Leiden) and human cholesteryl ester transfer protein (CETP), fed a cholesterol-enriched diet for 18 weeks, received an intravenous injection of LNP-encapsulated siRNA targeting Vwf (siVwf) or scrambled control siRNA at 1.5 mg siRNA/kg. For comparison, the same LNP-siRNAs were administered to young, chow-fed WT mice. Plasma VWF and Vwf mRNA levels were measured 96 hours after injection, with immunofluorescence analysis of lungs and heart aortic root to assess VWF protein expression. Results: APOE∗3-Leiden.CETP mice exhibited elevated plasma VWF levels compared with WT mice, alongside hypercholesterolemia and aortic atherosclerosis. siVwf administration led to over 85% reduction in plasma VWF in both strains, with a strong reduction in lung Vwf mRNA and VWF protein in the pulmonary endothelium. Similarly, siVwf treatment resulted in the virtual absence of VWF protein in the endothelial lining of the aortic root of both nondiseased (WT mice) and atherosclerotic (APOE∗3-Leiden.CETP mice) vessel walls. Conclusion: The LNP-siRNA targeting Vwf strongly reduced plasma and endothelial VWF in mice with hypercholesterolemia and advanced atherosclerosis, indicating feasibility to target endothelial VWF under proatherothrombotic conditions. |
| format | Article |
| id | doaj-art-8f43e381eba447d782d3c31a552e14bd |
| institution | DOAJ |
| issn | 2475-0379 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj-art-8f43e381eba447d782d3c31a552e14bd2025-08-20T03:04:38ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792025-01-019110269910.1016/j.rpth.2025.102699Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic miceYvonne K. Jongejan0Richard J. Dirven1Elisa Schrader Echeverri2Anke J.L. de Jong3Amanda C.M. Pronk4Sander Kooijman5Patrick C.N. Rensen6James E. Dahlman7Jeroen C.J. Eikenboom8Bart J.M. van Vlijmen9Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, NetherlandsDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, NetherlandsWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, USADivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, NetherlandsDivision of Endocrinology, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, NetherlandsDivision of Endocrinology, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, NetherlandsDivision of Endocrinology, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, NetherlandsWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, USADivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, NetherlandsDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands; Correspondence Bart J. M. van Vlijmen, Division of Thrombosis and Haemostasis, Department of Internal Medicine, Leiden University Medical Center, Einthoven Laboratory for Vascular and Regenerative Medicine, P.O. Box 9600, 2300 RC Leiden, Netherlands.Background: Elevated von Willebrand factor (VWF) levels correlate with higher risk of atherosclerosis-related arterial thrombosis (atherothrombosis). Silencing the VWF gene via small-interfering RNAs (siRNAs) could mitigate this risk. Previous studies successfully delivered siRNA to the endothelium of healthy, wild-type (WT) mice using lipid nanoparticles (LNPs). Objectives: This study aimed to investigate whether the LNP-siRNA strategy could achieve endothelium-specific Vwf-silencing under diseased conditions of prolonged hypercholesterolemia and atherothrombosis-prone vasculature. Methods: Female transgenic mice expressing a variant of human APOE∗3 (ie, APOE∗3-Leiden) and human cholesteryl ester transfer protein (CETP), fed a cholesterol-enriched diet for 18 weeks, received an intravenous injection of LNP-encapsulated siRNA targeting Vwf (siVwf) or scrambled control siRNA at 1.5 mg siRNA/kg. For comparison, the same LNP-siRNAs were administered to young, chow-fed WT mice. Plasma VWF and Vwf mRNA levels were measured 96 hours after injection, with immunofluorescence analysis of lungs and heart aortic root to assess VWF protein expression. Results: APOE∗3-Leiden.CETP mice exhibited elevated plasma VWF levels compared with WT mice, alongside hypercholesterolemia and aortic atherosclerosis. siVwf administration led to over 85% reduction in plasma VWF in both strains, with a strong reduction in lung Vwf mRNA and VWF protein in the pulmonary endothelium. Similarly, siVwf treatment resulted in the virtual absence of VWF protein in the endothelial lining of the aortic root of both nondiseased (WT mice) and atherosclerotic (APOE∗3-Leiden.CETP mice) vessel walls. Conclusion: The LNP-siRNA targeting Vwf strongly reduced plasma and endothelial VWF in mice with hypercholesterolemia and advanced atherosclerosis, indicating feasibility to target endothelial VWF under proatherothrombotic conditions.http://www.sciencedirect.com/science/article/pii/S2475037925000238atherothrombosishypercholesterolemiamouse modelsiRNAvon Willebrand factor |
| spellingShingle | Yvonne K. Jongejan Richard J. Dirven Elisa Schrader Echeverri Anke J.L. de Jong Amanda C.M. Pronk Sander Kooijman Patrick C.N. Rensen James E. Dahlman Jeroen C.J. Eikenboom Bart J.M. van Vlijmen Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic mice Research and Practice in Thrombosis and Haemostasis atherothrombosis hypercholesterolemia mouse model siRNA von Willebrand factor |
| title | Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic mice |
| title_full | Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic mice |
| title_fullStr | Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic mice |
| title_full_unstemmed | Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic mice |
| title_short | Silencing of the von Willebrand factor gene in proatherothrombotic APOE∗3-Leiden.CETP transgenic mice |
| title_sort | silencing of the von willebrand factor gene in proatherothrombotic apoe∗3 leiden cetp transgenic mice |
| topic | atherothrombosis hypercholesterolemia mouse model siRNA von Willebrand factor |
| url | http://www.sciencedirect.com/science/article/pii/S2475037925000238 |
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