BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators (PAs) and plays a role in the regulation of a number of physiological processes including the degradation of extracellular matrix proteins, cell proliferation and migration, and intracellular signaling. AIM: To characterize the effects of durable expression of a stable form of human PAI-1 and to characterize important structure-function relationships in PAI-1 in vivo. METHODS: We developed transgenic mice lines overexpressing stable variants of human PAI-1 under the control of the murine preproendothelin-1 promoter and characterized the phenotypic alterations displayed by transgenic mice. RESULTS: Transgenic mice expressing an active form of human PAI-1 (PAI-1-stab) display complex phenotypic abnormalities including alopecia and hepatosplenomegaly. Reactive site mutant transgenic mice expressing inactive PAI-1 exhibit complete phenotypic rescue, while transgenic mice expressing PAI-1 with reduced affinity for vitronectin manifest all of the phenotypic abnormalities present in PAI-1-stab transgenic mice. CONCLUSIONS: The protease inhibitory activity of PAI-1 toward PAs and/or other serine proteases is necessary and sufficient to promote complex phenotypic abnormalities and mediates many of the physiological effects of PAI-1 in vivo.
BACKGROUND:Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators (PAs) and plays a role in the regulation of a number of physiological processes including the degradation of extracellular matrix proteins, cell proliferation and migration, and intracellular signaling. AIM: To characterize the effects of durable expression of a stable form of humanPAI-1 and to characterize important structure-function relationships in PAI-1 in vivo. METHODS: We developed transgenic mice lines overexpressing stable variants of humanPAI-1 under the control of the murinepreproendothelin-1 promoter and characterized the phenotypic alterations displayed by transgenic mice. RESULTS:Transgenic mice expressing an active form of humanPAI-1 (PAI-1-stab) display complex phenotypic abnormalities including alopecia and hepatosplenomegaly. Reactive site mutant transgenic mice expressing inactive PAI-1 exhibit complete phenotypic rescue, while transgenic mice expressing PAI-1 with reduced affinity for vitronectin manifest all of the phenotypic abnormalities present in PAI-1-stabtransgenic mice. CONCLUSIONS: The protease inhibitory activity of PAI-1 toward PAs and/or other serine proteases is necessary and sufficient to promote complex phenotypic abnormalities and mediates many of the physiological effects of PAI-1 in vivo.
Authors: Anthony J Courey; Jeffrey C Horowitz; Kevin K Kim; Timothy J Koh; Margaret L Novak; Natalya Subbotina; Mark Warnock; Bing Xue; Andrew K Cunningham; Yujing Lin; Monica P Goldklang; Richard H Simon; Daniel A Lawrence; Thomas H Sisson Journal: Blood Date: 2011-07-06 Impact factor: 22.113
Authors: Amanda E Boe; Mesut Eren; Sheila B Murphy; Christine E Kamide; Atsuhiko Ichimura; David Terry; Danielle McAnally; Layton H Smith; Toshio Miyata; Douglas E Vaughan Journal: Circulation Date: 2013-10-03 Impact factor: 29.690