title: TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death.
abstract: Besides its well-recognized role in hemostasis and thrombosis, thromboxane A(2) synthase (TXAS) is proposed to be involved in thrombopoiesis and lymphocyte differentiation. To evaluate its various physiologic roles, we generated TXAS-deleted mice by gene targeting. TXAS(-/-) mice had normal bone marrow megakaryocytes, normal blood platelet counts, and normal CD4 and CD8 lymphocyte counts in thymus and spleen. Platelets from TXAS(-/-) mice failed to aggregate or generate thromboxane B(2) in response to arachidonic acid (AA) but produced increased prostaglandin-E(2) (PGE(2)), PGD(2), and PGF(2 alpha). AA infusion caused a progressive drop of mean arterial pressure (MAP), cardiac arrest, and death in wild-type (WT) mice but did not induce shock in TXAS(-/-) mice or in WT and TXAS(-/-) mice treated with antagonist to the thromboxane-prostanoid (TP) receptor. The TXAS(-/-) mice were able to maintain normal MAP upon AA insult when TP was present but were unable to do so when TP was blocked by an antagonist, suggesting a role of endoperoxide accumulation in influencing MAP. We conclude that TXAS is not essential for thrombopoiesis and lymphocyte differentiation. Its deficiency causes a mild hemostatic defect and protects mice against arachidonate-induced shock and death. The TXAS-deleted mice will be valuable for investigating the roles of arachidonate metabolic shunt in various pathophysiologic processes.
authors.affiliation: Graduate Institute of Medical Technology, Department of Pathology, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan.
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.forename: Shu-Rung
authors.initials: SR
authors.lastname: Lin
authors.forename: Chin-Chin
authors.initials: CC
authors.lastname: Huang
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Tseng
authors.forename: Pei-Hsing
authors.initials: PH
authors.lastname: Huang
authors.forename: Guey-Yueh
authors.initials: GY
authors.lastname: Shi
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
authors.forename: Chi-Lu
authors.initials: CL
authors.lastname: Tang
authors.forename: Pao-Hsien
authors.initials: PH
authors.lastname: Chu
authors.forename: Lee-Ho
authors.initials: LH
authors.lastname: Wang
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology*; D001760:Bleeding Time; D017353:Gene Deletion; D018390:Gene Targeting; D005838:Genotype; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006487:Hemostasis / Q000235:genetics / Q000502:physiology; D007527:Isoenzymes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology; D034061:Thrombopoiesis / Q000235:genetics / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D016718:Arachidonic Acid; D013930:Thromboxane-A Synthase