TY - JOUR
T1 - Atherothrombosis model by silencing of protein C in APOE*3-Leiden.CETP transgenic mice
AU - Jongejan, Yvonne K.
AU - Eikenboom, Jeroen C. J.
AU - Gijbels, Marion J. J.
AU - Berbée, Jimmy F. P.
AU - van Vlijmen, Bart J. M.
N1 - Funding Information: YKJ and JCJE declare to be financially supported by the Dutch Thrombosis Foundation. JCJE declares to be financially supported by CSL Behring. The other authors declare no competing financial interests. Funding Information: The authors thank Isabel M. Mol and Amanda C.M. Pronk for their technical assistance. This work was financially supported by Dutch Thrombosis Foundation (grant #2018-1). Publisher Copyright: © 2021, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - Apolipoprotein E3
KW - Atherosclerosis
KW - Mice
KW - Protein C
KW - Thrombosis
UR - http://www.scopus.com/inward/record.url?scp=85106984070&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s11239-021-02488-2
DO - https://doi.org/10.1007/s11239-021-02488-2
M3 - Article
C2 - 34052976
SN - 0929-5305
VL - 52
SP - 715
EP - 719
JO - Journal of Thrombosis and Thrombolysis
JF - Journal of Thrombosis and Thrombolysis
IS - 3
ER -