Tissue factor deficiency cause's cardiac fibrosis and left ventricular dysfunction

被引:87
作者
Pawlinski, R
Fernandes, A
Kehrle, B
Pedersen, B
Parry, G
Erlich, J
Pyo, R
Gutstein, D
Zhang, J
Castellino, F
Melis, E
Carmeliet, P
Baretton, G
Luther, T
Taubman, M
Rosen, E
Mackman, N
机构
[1] The Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[2] The Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA
[3] Univ New S Wales, Dept Nephrol, Sydney, NSW 2052, Australia
[4] Mt Sinai Med Ctr, Dept Med & Mol Biol, New York, NY 10029 USA
[5] Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium
[6] Tech Univ, Univ Klinikum Carl Gustav Carus, Inst Pathol, D-01307 Dresden, Germany
[7] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
关键词
D O I
10.1073/pnas.242501899
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that mice expressing low levels of human TF (approximate to1% of wild-type levels) in an mTF(-/-) background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a selective heart defect that consisted of hemosiderin deposition and fibrosis. Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left ventricular function in 8-month-old low-TF mice compared with age-matched wild-type mice. Mice expressing low levels of murine FVII (approximate to1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, FIX-/- mice, a model of hemophilia B, had normal hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.
引用
收藏
页码:15333 / 15338
页数:6
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