Ticagrelor promotes atherosclerotic plaque stability in a mouse model of advanced atherosclerosis.
OBJECTIVE
There is increasing evidence supporting the role of platelets in atherosclerotic vascular disease. The G-protein-coupled receptor P2Y12 is a central mediator of platelet activation and aggregation but has also been linked to platelet-independent vascular disease. Ticagrelor is an oral P2Y12 antagonist that is used as a standard treatment in patients after acute myocardial infarction. However, the effects of ticagrelor on advanced atherosclerosis have not been investigated.


METHODS
Twenty-week-old apolipoprotein-E-deficient mice received standard chow or standard chow supplemented with 0.15% ticagrelor (approximately 270 mg/kg/day) for 25 weeks. The lesion area was evaluated in the aortic sinus by Movat's pentachrome staining and lesion composition, thickness of the fibrous cap, and size of the necrotic core evaluated by morphometry. RAW 264.7 macrophages were serum starved and treated with ticagrelor in vitro for the detection and quantification of apoptosis. In addition, oxLDL uptake in RAW 264.7 macrophages was evaluated.


RESULTS
A trend toward the reduction of total lesion size was detected. However, data did not reach the levels of significance (control, n=11, 565,881 μm(2) [interquartile range {IQR} 454,778-603,925 μm(2)] versus ticagrelor, n=13, 462,595 μm(2) [IQR 379,740-546,037 μm(2)]; P=0.1). A significant reduction in the relative area of the necrotic core (control, n=11, 0.46 [IQR 0.4-0.51] versus ticagrelor, n=13, 0.34 [IQR 0.31-0.39]; P=0.008), and a significant increase in fibrous caps thickness (control, n=11, 3.7 μm [IQR 3.4-4.2 μm] versus ticagrelor, n=13, 4.7 [IQR 4.3-5.5 μm], P=0.04) were seen in ticagrelor-treated mice. In vitro studies demonstrated a reduction in apoptotic RAW 264.7 macrophages (control 0.07±0.03 versus ticagrelor 0.03±0.03; P=0.0002) when incubated with ticagrelor. Uptake of oxLDL in RAW 264.7 was significantly reduced when treated with ticagrelor (control 9.2 [IQR 5.3-12.9] versus ticagrelor 6.4 [IQR 2.5-9.5], P=0.02).


CONCLUSIONS
The present study demonstrates for the first time a plaque-stabilizing effect of ticagrelor in a model of advanced vascular disease, potentially induced by a reduction of oxLDL uptake or an inhibition of apoptosis as seen in vitro.
Department of Internal Medicine III.
Michael R
MR
Preusch
Department of Internal Medicine III.
Jonas
J
Rusnak
Department of Neonatology.
Kathrin
K
Staudacher
Department of Pathology.
Carolin
C
Mogler
Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
Lorenz
L
Uhlmann
Department of Internal Medicine III.
Philipp
P
Sievers
Department of Internal Medicine III.
Florian
F
Bea
Department of Internal Medicine III.
Hugo A
HA
Katus
Department of Internal Medicine III.
Erwin
E
Blessing
Department of Internal Medicine III.
Ingo
I
Staudacher
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D000077486:Ticagrelor
D001057:Apolipoproteins E; D000077486:Ticagrelor; D000241:Adenosine
P2Y12; apoE mouse; apoptosis; atherosclerosis; inflammation; oxLDL; platelets; ticagrelor