HIF-1α represses the expression of the angiogenesis inhibitor thrombospondin-2.
HIF-1α represses the expression of the angiogenesis inhibitor thrombospondin-2.
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DOI：
10.1016/j.matbio.2017.07.002
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Kyriakides TR
中科院分区：
文献类型：
--
作者：
MacLauchlan SC;Calabro NE;Huang Y;Krishna M;Bancroft T;Sharma T;Yu J;Sessa WC;Giordano F;Kyriakides TR
血小板反应素-2（TSP 2）是一种有效的血管生成抑制剂，其表达在损伤后受到动态调节。在本研究中，它表明，HIF-1α抑制TSP 2转录。具体地，体外研究表明脯氨酰羟化酶抑制剂DMOG或缺氧降低成纤维细胞中的TSP 2表达。这种效应显示是通过转录机制，因为缺氧不会改变TSP 2 mRNA的稳定性，并且这种效应需要TSP 2启动子。此外，一氧化氮（NO）对TSP 2的抑制作用被证明是非典型的，涉及缺氧诱导因子-1 α（HIF-1α）的稳定。TSP 2通过缺氧的调节得到以下体内观察的支持：TSP 2在小鼠后肢缺血（HLI）后的腓肠肌中具有不同于缺氧区域的时空表达。HLI后SM 22 α-cre HIF-1α KO小鼠中TSP 2表达失调支持HIF-1α对TSP 2的调节作用。事实上，与同窝对照相比，HLI手术后SM 22 a-cre HIF-1α KO小鼠的血流恢复减少，与恢复受损和TSP 2水平升高相关。此外，SM 22 α-cre HIF-1α KO平滑肌细胞小鼠具有增加的TSP 2 mRNA水平，其在缺氧中持续存在。这些发现确定了一种新的缺血诱导的促血管生成机制，涉及HIF-1α对TSP 2的转录抑制。
Thrombospondin-2 (TSP2) is a potent inhibitor of angiogenesis whose expression is dynamically regulated following injury. In the present study, it is shown that HIF-1α represses TSP2 transcription. Specifically, in vitro studies demonstrate that the prolyl hydroxylase inhibitor DMOG or hypoxia decrease TSP2 expression in fibroblasts. This effect is shown to be via a transcriptional mechanism as hypoxia does not alter TSP2 mRNA stability and this effect requires the TSP2 promoter. In addition, the documented repressive effect of nitric oxide (NO) on TSP2 is shown to be non-canonical and involves stabilization of hypoxia inducible factor-1a (HIF-1α). The regulation of TSP2 by hypoxia is supported by the in vivo observation that TSP2 has spatiotemporal expression distinct from regions of hypoxia in gastrocnemius muscle following murine hindlimb ischemia (HLI). A role for TSP2 regulation by HIF-1α is supported by the dysregulation of TSP2 expression in SM22α-cre HIF-1α KO mice following HLI. Indeed, there is a reduction in blood flow recovery in the SM22a-cre HIF-1α KO mice compared to littermate controls following HLI surgery, associated with impaired recovery and increased TSP2 levels. Moreover, SM22α-cre HIF-1α KO smooth muscle cells mice have increased TSP2 mRNA levels that persist in hypoxia. These findings identify a novel, ischemia-induced pro-angiogenic mechanism involving the transcriptional repression of TSP2 by HIF-1α.
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影响因子：
2.7
作者：
Kotch, LE;Iyer, NV;Semenza, GL
通讯作者：
Semenza, GL
影响因子：
20.3
作者：
Kristofik, Nina;Calabro, Nicole E.;Kyriakides, Themis R.
通讯作者：
Kyriakides, Themis R.
缺乏血小板反应蛋白 2 的小鼠表现出结缔组织异常，这与胶原纤维生成紊乱、血管密度增加和出血素质有关。
影响因子：
7.8
作者：
Kyriakides, T R;Zhu, Y H;Smith, L T;Bain, S D;Yang, Z;Lin, M T;Danielson, K G;Iozzo, R V;LaMarca, M;McKinney, C E;Ginns, E I;Bornstein, P
通讯作者：
Bornstein, P
影响因子：
4.8
作者：
Kasuno, K;Takabuchi, S;Hirota, K
通讯作者：
Hirota, K
影响因子：
10.5
作者：
Iyer, NV;Kotch, LE;Semenza, GL
通讯作者：
Semenza, GL