thromboplastin and Endomyocardial-Fibrosis

Tissue factor (TF) is the cellular receptor and cofactor for blood coagulation factor VII (FVII). Exposure of flowing blood to cells that express TF leads to the initiation of blood coagulation. A recent study of mice expressing low levels of TF has demonstrated the importance of TF and FVII in maintaining adequate haemostasis within the heart. In addition, the study indicates that the heart is subject to a succession of minor bleeds most probably as a result of repetitive minor mechanical injury to the blood vessels.

Topics: Animals; Blood Coagulation; Endomyocardial Fibrosis; Factor VII; Gene Expression; Heart; Hemorrhagic Disorders; Hemosiderin; Hemostasis; Mice; Myocardial Contraction; Thromboplastin

Tissue factor (TF) initiates the protease coagulation cascade in response to tissue injury. Homozygous deficiency of murine TF results in embryonic lethality, which is rescued by low-level expression of human TF. These low-TF mice have been shown to develop cardiac fibrosis. We tested the hypothesis that the development of cardiac fibrosis in low-TF mice results from dysregulated protease expression and is affected by gender. Mice were divided into the age groups 2-5, 6-12, 13-18 and 19+ weeks. Fibrosis was assessed by trichrome staining. Protease expression was measured in male and female mice by RT-PCR for mRNA and zymography, ELISA or immunoblot for protein. Urokinase plasminogen activator (uPA) activity was determined by zymography and chromogenic substrate assay. A marked gender effect was noted for the development of fibrosis, with interstitial collagen deposition occurring from 9 weeks in male low-TF mice, but not until 19 weeks in low-TF females. This delayed onset in females was accompanied by delayed up-regulation of molecular markers of injury. Matrix metalloproteinase (MMP)-3 and tissue inhibitor of metalloproteinase (TIMP)-1 expression were up-regulated in the hearts of male low-TF mice from 6 to 12 weeks and in females from 19 weeks. MMP/TIMP dysregulation was not seen prior to cardiac fibrosis and did not appear to explain the gender differences. However, uPA expression and activity were down-regulated prior to cardiac fibrosis in low-TF females, but were up-regulated in age-matched males. This suggests that the down-regulation of uPA in female low-TF mice protects them from more severe cardiac fibrosis.

Topics: Animals; Biomarkers; Connective Tissue Growth Factor; Down-Regulation; Endomyocardial Fibrosis; Female; Humans; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Male; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; RNA, Messenger; Sex Characteristics; Thromboplastin; Tissue Inhibitor of Metalloproteinases; Up-Regulation; Urokinase-Type Plasminogen Activator

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 ( approximately 1% 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 ( approximately 1% 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.

Topics: Animals; Endomyocardial Fibrosis; Factor VII; Fibrinogen; Gene Expression; Genetic Predisposition to Disease; Hemophilia B; Hemorrhagic Disorders; Hemosiderin; Hemostasis; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Biological; Muscle, Skeletal; Myocardium; Organ Specificity; Protein Structure, Tertiary; Recombinant Fusion Proteins; Thromboplastin; Ventricular Dysfunction, Left