Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction.
Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction.
复制标题
DOI：
10.1038/ncb1811
复制
发表时间：
2009-01
影响因子：
21.3
通讯作者：
Sato, Thomas N.
中科院分区：
文献类型：
--
作者：
Kobayashi, Koichi;Luo, Min;Zhang, Yue;Wilkes, David C.;Ge, Gaoxiang;Grieskamp, Thomas;Yamada, Chikaomi;Liu, Ting-Chun;Huang, Guorui;Basson, Craig T.;Kispert, Andreas;Greenspan, Daniel S.;Sato, Thomas N.
分泌卷曲相关蛋白(SFRPs)已成为广泛的发育和疾病过程的关键调节因子，哺乳动物sFRPs的几乎所有已知功能都归因于它们拮抗Wnt信号的能力。然而，最近，非洲爪哇和斑马鱼的SFRP被证明是Tolloid类金属蛋白酶加工Chordin的拮抗剂，这导致了sFRPs可能作为这类酶的Chordin酶活性的进化保守的拮抗剂发挥作用。在这里，与这一建议相反，我们证明了哺乳动物的SFRP，SFRP2，不影响Chordin的加工，而是可以作为Tolloid样金属蛋白酶的前胶原C-蛋白酶活性的直接增强剂。我们进一步表明，在SFRP2基因缺失的小鼠中，心肌梗死后的纤维化水平显著降低，其中Tolloid样蛋白酶对前胶原的处理起到了限速作用。重要的是，纤维化水平的降低伴随着心功能的显著改善。因此，这项研究揭示了SFRP2的一种新功能，以及SFRP2拮抗在控制心肌梗死纤维化中的潜在治疗应用。
Secreted frizzled related proteins (sFRPs) have emerged as key regulators of a wide range of developmental and disease processes, with virtually all known functions of mammalian sFRPs attributed to their ability to antagonize Wnt signaling. Recently however, the Xenopus and zebrafish sFRP, Sizzled, was shown to function as an antagonist of Chordin processing by Tolloid-like metalloproteinases, leading to the proposal that sFRPs may function as evolutionarily-conserved antagonists of the chordinase activities of this class of proteinases. Herein, in contrast to this proposal, we show that the mammalian sFRP, sFRP2, does not affect Chordin processing, but instead can serve as a direct enhancer of the procollagen C-proteinase activity of Tolloid-like metalloproteinases. We further show that the level of fibrosis, in which procollagen processing by Tolloid-like proteinases plays a rate-limiting role, is markedly reduced in sFRP2-null mice subjected to myocardial infarction. Importantly, this reduced level of fibrosis is accompanied by significantly improved cardiac function. This study thus uncovers a novel function for sFRP2 and a potential therapeutic application for sFRP2 antagonism in controlling fibrosis in the infarcted heart.
登录
查看更多内容
NTR模块：netrins、分泌型frizzled相关蛋白和I型胶原蛋白C蛋白酶增强蛋白的结构域与金属蛋白酶组织抑制剂同源
影响因子：
8
作者：
Bányai, L;Patthy, L
通讯作者：
Patthy, L
DOI：
10.1073/pnas.0704179104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Ge, Gaoxiang;Fernandez, Cecilia A.;Greenspan, Daniel S.
通讯作者：
Greenspan, Daniel S.
影响因子：
--
作者：
Bodine, PVN;Zhao, WG;Komm, BS
通讯作者：
Komm, BS
DOI：
10.1073/pnas.94.25.13636
发表时间：
1997-12-09
影响因子：
11.1
作者：
Melkonyan, HS;Chang, WC;Umansky, SR
通讯作者：
Umansky, SR
DOI：
10.1073/pnas.94.13.6770
发表时间：
1997-06-24
影响因子：
11.1
作者：
Finch, PW;He, X;Rubin, JS
通讯作者：
Rubin, JS