Silencing of Anticoagulant Protein C Evokes Low-Incident but Spontaneous Atherothrombosis in Apolipoprotein E–Deficient Mice—Brief Report

Ouweneel, Amber B.; Heestermans, Marco; Verwilligen, Robin A.F.; Gijbels, Marion J.J.; Reitsma, Pieter H.; Eck, Miranda Van; Vlijmen, Bart J.M. van

doi:10.1161/atvbaha.117.309188

Cited by 8 publications

(25 citation statements)

References 10 publications

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“…At the time of sacrifice, all Apoe −/− mice treated with PBS or phenylephrine (PE) and siRNA (both siNEG and siProc) appeared healthy and did not show any abnormalities. Histological analysis of the aortic root of 10 weeks WTD-fed siProc treated mice demonstrated the presence of atherosclerotic plaque-associated thrombi, with a similar size and composition as previously reported 9 . In total, 9 out of 39 siProc treated Apoe −/− mice (23.0%, CI (95%): 16.7-47.9) were categorized as atherothrombosis-positive in the aortic root (siProc + THR, Figs 1A-D and 2).…”

Section: Resultssupporting

confidence: 82%

“…In our previous study 9 , we found no significant correlation between plaque size and phenotype and the susceptibility to aortic root atherothrombosis. However, with only 4 siProc + THR mice the power in that study was low.…”

Section: Resultsmentioning

confidence: 55%

“…Recently, we showed that transient (7 days) siRNA mediated lowering of the natural anticoagulant protein C (siProc) in atherosclerotic Apoe −/− mice induced superimposed thrombus formation on atherosclerotic plaques in the aortic root 9 . Although the incidence of this unique phenotype was low (1 out of 4 and 3 out of 25 in two independent experiments, cumulative incidence of 14%), our novel mouse model might be of use to better understand the pathophysiology of atherothrombosis.…”

mentioning

confidence: 99%

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Predilection of low protein C-induced spontaneous atherothrombosis for the right coronary sinus in apolipoprotein E-deficient mice

et al. 2018

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Silencing of anticoagulant protein C using RNA interference (siProc) evokes low incident but spontaneous atherothrombosis in the aortic root of apolipoprotein E-deficient (Apoe −/−) mice. The aims of the current study were (1) to analyze if plaque characteristics or circulating factors could be linked to atherothrombosis susceptibility, (2) to increase the incidence of atherothrombosis by transiently increasing blood pressure, and (3) to direct atherothrombosis to an additional predefined vascular site by applying a semi-constrictive collar around the carotid artery. siProc-driven spontaneous atherothrombosis in the aortic root of Apoe −/− mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe −/− mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, serum amyloid A, and IL-6 were not different amongst siProc treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe −/− mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 55%

mentioning

confidence: 99%

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Predilection of low protein C-induced spontaneous atherothrombosis for the right coronary sinus in apolipoprotein E-deficient mice

et al. 2018

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“…Despite commonly used murine model of atherosclerosis is resistant to thrombus formation, silencing of protein C in apolipoprotein E-deficient mice with small interfering RNA allows occurrence of spontaneous atherothrombosis at low incidence. 41 It is unclear whether this prothrombotic effect is only attributed to the anticoagulation of activated protein C 42 or also to its cytoprotective effects in anti-inflammation, antiapoptosis, and stabilization of endothelial barriers.…”

Section: Protein Cmentioning

confidence: 99%

Thrombotic Regulation From the Endothelial Cell Perspectives

Wang

Hao

Leeper

et al. 2018

ATVB

130

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“…Recently, we showed that transient (7 days) siRNA mediated lowering of the natural anticoagulant protein C (si Proc ) in atherosclerotic Apoe −/− mice induced superimposed thrombus formation on atherosclerotic plaques in the aortic root 9 . Although the incidence of this unique phenotype was low (1 out of 4 and 3 out of 25 in two independent experiments, cumulative incidence of 14%), our novel mouse model might be of use to better understand the pathophysiology of atherothrombosis.…”

Section: Introductionmentioning

confidence: 99%

Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E deficient mice

Heestermans

Ouweneel

Hassan

et al. 2018

Sci Rep

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Silencing of anticoagulant protein C using RNA interference (siProc) evokes low incident but spontaneous atherothrombosis in the aortic root of apolipoprotein E–deficient (Apoe−/−) mice. The aims of the current study were (1) to analyze if plaque characteristics or circulating factors could be linked to atherothrombosis susceptibility, (2) to increase the incidence of atherothrombosis by transiently increasing blood pressure, and (3) to direct atherothrombosis to an additional predefined vascular site by applying a semi-constrictive collar around the carotid artery. siProc-driven spontaneous atherothrombosis in the aortic root of Apoe−/− mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe−/− mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, serum amyloid A, and IL-6 were not different amongst siProc treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe−/− mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.

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Silencing of Anticoagulant Protein C Evokes Low-Incident but Spontaneous Atherothrombosis in Apolipoprotein E–Deficient Mice—Brief Report

Cited by 8 publications

References 10 publications

Predilection of low protein C-induced spontaneous atherothrombosis for the right coronary sinus in apolipoprotein E-deficient mice

Predilection of low protein C-induced spontaneous atherothrombosis for the right coronary sinus in apolipoprotein E-deficient mice

Thrombotic Regulation From the Endothelial Cell Perspectives

Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E deficient mice

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