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The development of cardiac fibrosis in low tissue factor mice is gender-dependent and is associated with differential regulation of urokinase plasminogen activator.
Journal of Molecular and Cellular Cardiology ( IF 5 ) Pub Date : 2007-01-20 , DOI: 10.1016/j.yjmcc.2006.11.017
Darren R Davis 1 , Kate Wilson , Melissa J Sam , Sean E Kennedy , Nigel Mackman , John A Charlesworth , Jonathan H Erlich
Affiliation  

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.

中文翻译:

低组织因子小鼠心脏纤维化的发展与性别有关,并与尿激酶纤溶酶原激活剂的差异调节有关。

组织因子(TF)响应组织损伤而启动蛋白酶凝结级联反应。鼠TF的纯合子缺乏导致胚胎致死性,其通过人TF的低水平表达得以挽救。这些低TF小鼠已显示出心脏纤维化。我们测试了一个假设,即低TF小鼠心脏纤维化的发展是由蛋白酶表达失调引起的,并且受性别的影响。将小鼠分为2-5、6-12、13-18和19+周龄。通过三色染色评估纤维化。通过RT-PCR检测mRNA和酶谱,ELISA或蛋白质免疫印迹法测定雄性和雌性小鼠中的蛋白酶表达。尿激酶纤溶酶原激活剂(uPA)的活性通过酶谱法和生色底物测定法确定。注意到明显的性别影响是纤维化的发展,在雄性低TF小鼠中,胶原蛋白的沉积从9周开始,而在雌性低TF小鼠中,直到19周才发生。女性的这种延迟发作伴随着损伤分子标志物的上调延迟。雄性低TF小鼠的心脏从6到12周和雌性从19周开始,基质金属蛋白酶(MMP)-3和组织金属蛋白酶(TIMP)-1的表达被上调。在心脏纤维化之前未见MMP / TIMP失调,也未解释性别差异。然而,低TF女性在心脏纤维化之前uPA表达和活性被下调,而年龄匹配的男性uPA表达和活性被上调。这表明在雌性低TF小鼠中uPA的下调保护了它们免受更严重的心脏纤维化的影响。
更新日期:2019-11-01
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