title: A Potential Mechanism of High-Dose Ticagrelor in Modulating Platelet Activity and Atherosclerosis Mediated by Thymic Stromal Lymphopoietin Receptor.
abstract: Abnormal expression of thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) was found in patients with acute coronary syndrome. Ticagrelor, an oral platelet ADP P2Y12 receptor antagonist, is widely used in these patients. The aim of this study was to verify whether different doses of ticagrelor regulated plaque progression and platelet activity by modulating TSLP/TSLPR. Seventy-five ApoE-/- mice were randomly divided into five groups: (1) high-cholesterol diet (HCD, n = 15); (2) HCD plus ticagrelor 25 mg/kg/d (T1, n = 15); (3) HCD plus ticagrelor 50 mg/kg/d (T2, n = 15); (4) HCD plus ticagrelor 100 mg/kg/d (T3, n = 15); and (5) a normal diet group (ND, n = 15). At day 0 and at week 16, blood lipids and serum TSLP levels, expression of TSLPR, CD62, and CD63, platelet aggregation, platelet ATP release, PI3K/Akt signaling pathway, and plaque morphology were assessed. HCD increased TSLPR expression and atherosclerosis progression but high-dose ticagrelor (100 mg/kg) moderated this trend. TSLPR was positively correlated with Akt1, platelet aggregation, corrected plaque area, and vulnerability index in the T3 group (P<0.01). In conclusion, low-dose ticagrelor only inhibited platelet activity. Besides this inhibition, high-dose ticagrelor modulated platelet activity and atherosclerosis mediated by TSLPR, potentially through the PI3K/Akt signal pathway.
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Qiutang
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Longxian
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Boyuan
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Meng
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Yitian
authors.initials: Y
authors.lastname: Lian
authors.affiliation: Department of Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, PR China.
authors.forename: Dazhu
authors.initials: D
authors.lastname: Li
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D002791:Cholesterol, Dietary / Q000633:toxicity; D016207:Cytokines / Q000097:blood / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000188:drug therapy; D007136:Immunoglobulins / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D060149:Tetraspanin 30 / Q000097:blood; D000077486:Ticagrelor; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D001057:Apolipoproteins E; C554587:Cd63 protein, mouse; D002791:Cholesterol, Dietary; D016207:Cytokines; D007136:Immunoglobulins; D008055:Lipids; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D018121:Receptors, Cytokine; D060149:Tetraspanin 30; C410591:Tslpr protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D000077486:Ticagrelor; D000241:Adenosine; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse