| First Author | Davis DR | Year | 2007 |
| Journal | J Mol Cell Cardiol | Volume | 42 |
| Issue | 3 | Pages | 559-71 |
| PubMed ID | 17234207 | Mgi Jnum | J:119522 |
| Mgi Id | MGI:3702372 | Doi | 10.1016/j.yjmcc.2006.11.017 |
| Citation | Davis DR, et al. (2007) The development of cardiac fibrosis in low tissue factor mice is gender-dependent and is associated with differential regulation of urokinase plasminogen activator. J Mol Cell Cardiol 42(3):559-71 |
| abstractText | 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. |
