期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 163, 期 8, 页码 1666-1678出版社
WILEY
DOI: 10.1111/j.1476-5381.2010.01146.x
关键词
serine protease; prolyl oligopeptidase inhibitor; Ac-SDKP; thymosin beta 4; tumour angiogenesis
资金
- Academy of Finland [210758, 1131915]
- Helsinki University
- Sigrid Juselius Foundation
- Finnish Cultural Foundation
- Academy of Finland (AKA) [210758, 210758] Funding Source: Academy of Finland (AKA)
BACKGROUND AND PURPOSE A serine protease, prolyl oligopeptidase (POP) has been reported to be involved in the release of the pro-angiogenic tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (Ac-SDKP) from its precursor, 43-mer thymosin beta 4 (T beta 4). Recently, it was shown that both POP activity and the levels of Ac-SDKP are increased in malignant tumours. The aim of this study was to clarify the release of Ac-SDKP, and test if POP and a POP inhibitor, 4-phenyl-butanoyl-L-prolyl-2(S)-cyanopyrrolidine (KYP-2047), can affect angiogenesis. EXPERIMENTAL APPROACH We used HPLC for bioanalytical and an enzyme immunoassay for pharmacological analysis. Angiogenesis of human umbilical vein endothelial cells was assessed in vitro using a 'tube formation' assay and in vivo using a Matrigel plug assay (BD Biosciences, San Jose, CA, USA) in adult male rats. Moreover, co-localization of POP and blood vessels was studied. KEY RESULTS We showed the sequential hydrolysis of T beta 4: the first-step hydrolysis by proteases to <30-mer peptides is followed by an action of POP. Unexpectedly, POP inhibited the first hydrolysis step, revealing a novel regulation system. POP with T beta 4 significantly induced, while KYP-2047 effectively prevented, angiogenesis in both models compared with T beta 4 addition itself. POP and endothelial cells were abundantly co-localized in vivo. CONCLUSIONS AND IMPLICATIONS We have now revealed that POP is a second-step enzyme in the release of Ac-SDKP from T beta 4, and it has novel autoregulatory effect in the first step. Our results also advocate a role for Ac-SDKP in angiogenesis, and suggest that POP has a pro-angiogenic role via the release of Ac-SDKP from its precursor T beta 4 and POP inhibitors can block this action.
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