Cardiac tissue factor: roles in physiology and fibrosis.

1. The aim of the present review is to discuss: (i) the role of tissue factor (TF) in the heart and focus on its potential role in maintaining normal extracellular cardiac homeostasis; (ii) the means by which TF may be contributing to extracellular matrix regulation and vascular maintenance; and (iii) potential mechanisms whereby reduced TF expression leads to cardiac fibrosis. 2. Tissue factor is the main initiator of the coagulation cascade in response to tissue injury, but it is also involved in numerous other biological processes, including angiogenesis, cell migration, apoptosis, metastasis and inflammation. 3. Tissue factor is implicated in cardiovascular disease and its localization and level of expression in cardiomyocytes suggests a unique role in maintaining the structure and function of cardiac muscle. 4. It has been shown that TF(-/-) mice die in utero as a result of disrupted yolk sac vasculature. Low-TF mice, which have transgenic expression of TF at less than 1% of normal levels, are rescued from lethality. 5. Low-TF mice develop cardiac fibrosis in a gender-dependent manner that may be dependent on differential expression of urokinase plasminogen activator. 6. Intracardiac bleeding in low-TF mice may occur as a result of a primary haemostasis defect and/or as a result of disrupted vascular maintenance. The mechanism, when elucidated, will have important therapeutic implications and may provide novel strategies for the treatment of cardiac fibrosis.

The development of cardiac fibrosis in low tissue factor mice is gender-dependent and is associated with differential regulation of urokinase plasminogen activator.

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.

Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury.

Ischemia/reperfusion (IR) injury is a leading cause of acute renal failure and an important contributor to allograft damage. Tissue factor (TF) is up-regulated during IR, and TF inhibition reduces renal injury. However, the underlying mechanisms by which TF contributes to injury have not been elucidated. We postulated that TF contributes to IR injury by production of coagulation proteases and subsequent signaling by protease activated receptor (PARs). We compared renal injury after 25 minutes of bilateral renal ischemia and varying periods of reperfusion in C57BL/6 mice, those expressing low levels of TF (low-TF), hirudin-treated C57BL/6, and mice lacking either PAR-1 or PAR-2. C57BL/6 mice developed severe renal failure and died within 48 hours of reperfusion. In contrast, low-TF, hirudin-treated C57BL/6, and PAR-1-/- mice were protected from renal failure and had reduced mortality, tubular injury, neutrophil accumulation, and lower levels of the chemokines KC and MIP-2. Importantly, PAR-1-/- mice had lower chemokine levels despite up-regulation of TF and fibrin deposition. In addition, treating PAR-1-/- mice with hirudin conferred no additional benefit. Somewhat surprisingly, PAR-2 deficiency did not protect from renal failure. These experiments indicate that increased TF activity after renal IR leads to increased CXC chemokine expression and subsequent neutrophil-mediated injury predominantly by thrombin-dependent PAR-1 signaling.