Targeting plasminogen activator inhibitor-1: Role in cell signaling and the biology of domain-specific knock-in mice

被引:9
作者
Balsara, R. D.
Xui, Z.
Ploplis, V. A.
机构
[1] Univ Notre Dame, WM Keck Ctr Transgene Res, Notre Dame, IN 46556 USA
[2] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
[3] Univ Notre Dame, Notre Dame Canc Inst, Notre Dame, IN 46556 USA
关键词
plasminogen activator inhibitor-1; signaling pathways; diabetes; obesity; inflammation; hypoxia; functional domains; knock-in mice;
D O I
10.2174/138945007781662382
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
It is well documented that elevated levels of PAI-1 in plasma can decrease the fibrinolytic activity in blood with an associated increased risk of thrombus formation. A diverse range of molecules including bacterial lipopolysaccharide (LPS), the inflammatory mediators tumor necrosis factor a (TNF alpha) and interleukins, thrombin, transforming growth factor-beta (TGF-beta), and hormones regulate the synthesis of plasma PAI-1. Therefore, it is of clinical importance to restore the fibrinolytic balance. For a drug to be effective in controlling the synthesis of PAI-1, sufficient insight into the signal transduction pathways that control its regulation is desirable, which could serve as logical targets for the development of pharmaceuticals. Some key signaling pathways have been identified with the aid of pharmacological inhibitors, involved in the up-regulation of PAI-1 in context with several diseases, including obesity, insulin resistance, diabetic nephropathy, glomulonephritis, and pulmonary fibrosis. Furthermore, independent of its inhibitory activity PAI-1 mediates interactions with vitronectin (VN) and low density lipoprotein receptor-related protein (LRP) which modifies basic cell behaviors of proliferation, migration, and attachment. Intriguingly, it has been shown that both anti-fibrinolytic and non-fibrinolytic-related functions of PAI-1 may have overlapping roles in many diseases that are poorly understood. Tailoring knock-in mice with site-specific alterations that diminish the inhibitory activity, VN-binding, and LRP-binding activity of PAI-1 are useful tools for manipulation of biochemical properties, in vivo, and evaluating therapeutics.
引用
收藏
页码:982 / 995
页数:14
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