Longistatin, a novel plasminogen activator from vector ticks, is resistant to plasminogen activator inhibitor-1 |
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Authors: | Anisuzzaman Khyrul Islam M Abdul Alim M Miyoshi Takeharu Hatta Takeshi Yamaji Kayoko Matsumoto Yasunobu Fujisaki Kozo Tsuji Naotoshi |
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Institution: | aDepartment of Global Agricultural Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan;bNational Institute of Animal Health, National Agricultural and Food Research Organization, Tsukuba, Ibaraki, Japan;cDepartment of Veterinary Science, The University of Melbourne, Werribee, Victoria, Australia;dSchool of Frontier Veterinary Medicine, Kagoshima University, Kagoshima, Kagoshima, Japan |
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Abstract: | Thrombo-occlusive diseases are major causes of morbidity and mortality, and tissue-type plasminogen activator (t-PA) is recommended for the treatment of the maladies. However, both t-PA and u-PA are rapidly inactivated by plasminogen activator inhibitor-1 (PAI-1). Here, we show that longistatin, a novel plasminogen activator isolated from the ixodid tick, Haemaphysalis longicornis is resistant to PAI-1. Longistatin was relatively less susceptible to the inhibitory effect of SDS-treated platelet lysate than physiologic PAs. Platelet lysate inhibited t-PA and tcu-PA with the IC50 of 7.7 and 9.1 μg/ml, respectively, whereas for longistatin inhibition IC50 was 20.1 μg/ml (p < 0.01). Similarly, activated PAI-1 (20 nM) inhibited only 21.47% activity of longistatin but almost completely inhibited t-PA (99.17%) and tcu-PA (96.84%). Interestingly, longistatin retained 76.73% initial activity even after 3 h of incubation with 20 nM of PAI-1. IC50 of PAI-1 during longistatin inhibition was 88.3 nM while it was 3.9 and 3.2 nM in t-PA and tcu-PA inhibition, respectively. Longistatin completely hydrolyzed fibrin clot by activating plasminogen efficiently in the presence of 20 nM of PAI-1. Importantly, unlike t-PA, longistatin did not form complex with PAI-1. Collectively, our results suggest that longistatin is resistant to PAI-1 and maybe an interesting tool for the development of a PAI-1 resistant effective thrombolytic agent. |
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Keywords: | Abbreviations: t-PA tissue-type plasminogen activator u-PA urokinase-type plasminogen activator tcu-PA two chain u-PA serpin serine protease inhibitor PAI-1 plasminogen activator inhibitor-1 SDS&minus PAGE sodium dodecyl sulphate-polyacrylamide gel electrophoresis PRP platelet-rich plasma PPP platelet-poor plasma |
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