TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death.
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.
Yu
I-Shing
IS
Graduate Institute of Medical Technology, Department of Pathology, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan.
Lin
Shu-Rung
SR
Huang
Chin-Chin
CC
Tseng
Hui-Yu
HY
Huang
Pei-Hsing
PH
Shi
Guey-Yueh
GY
Wu
Hua-Lin
HL
Tang
Chi-Lu
CL
Chu
Pao-Hsien
PH
Wang
Lee-Ho
LH
Wu
Kenneth K
KK
Lin
Shu-Wha
SW
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
D007527:Isoenzymes; D016718:Arachidonic Acid; D013930:Thromboxane-A Synthase