Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction.
Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction.
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缺氧诱导的VEGF靶向胶原蛋白的基因传递有效改善心肌梗死后的心功能
DOI：
10.1038/s41598-017-13547-1
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发表时间：
2017-10-16
影响因子：
4.6
通讯作者：
Qi XF
中科院分区：
文献类型：
--
作者：
Xia JB;Wu HY;Lai BL;Zheng L;Zhou DC;Chang ZS;Mao CZ;Liu GH;Park KS;Zhao H;Kim SK;Song GH;Cai DQ;Qi XF
血管内皮生长因子（VEGF）在心肌梗死（MI）后心功能的改善中起重要作用。然而，缺乏靶向梗死心肌的VEGF的可操纵递送系统降低了治疗功效和安全性。本研究构建了一系列慢病毒载体系统，在低氧诱导启动子（5 HRE-hCMVmp，5 HRE）的调控下，表达由胶原结合域（CBD）和人血管内皮生长因子（hVEGF）组成的融合蛋白（CBDhVEGF）。我们证明了5 HRE在低氧条件下具有与普遍存在的CMV启动子相当的强烈驱动CBDhVEGF的能力，但在常氧条件下它几乎不能驱动靶基因。5 HRE驱动的CBDhVEGF与I型胶原特异性结合，显著促进HUVEC细胞的活力。心肌梗死小鼠心肌注射慢病毒后，CBDhVEGF主要滞留在心肌梗死区，胶原含量丰富，血管生成和心功能较hVEGF明显改善。此外，慢病毒介导的CBDhVEGF比hVEGF几乎没有从梗死区渗漏到血液中。综上所述，我们的研究结果表明，5 HRE-CBDhVEGF慢病毒载体系统可以通过胶原靶向和缺氧诱导的方式改善心脏功能。
Vascular endothelial growth factor (VEGF) plays important roles in improvement of cardiac function following myocardial infarction (MI). However, the lack of a steerable delivery system of VEGF targeting the infarcted myocardium reduces the therapeutic efficacy and safety. Here, we constructed a series of lentiviral vector systems which could express a fusion protein consisted of a collagen-binding domain (CBD) and hVEGF (CBDhVEGF), under the control of 5HRE-hCMVmp (5HRE), the hypoxia-inducible promoter consists of five copies of the hypoxia-responsive element (HRE) and a human cytomegalovirus minimal promoter (hCMVmp). We demonstrated that 5HRE has the comparable ability to strongly drive CBDhVEGF under hypoxic condition as the ubiquitous CMV promoter, but it can hardly drive target gene under normoxic condition. 5HRE-drived CBDhVEGF specifically bound to type I collagen and significantly promoted the viability of HUVEC cells. Moreover, after injection of lentivirus into heart of mouse with MI, CBDhVEGF was mainly retained in infarcted myocardium where containing rich collagen and significantly improved angiogenesis and cardiac function when compared with hVEGF. Moreover, CBDhVEGF mediated by lentivirus has little leakage from infarcted zone into blood than hVEGF. Taken together, our results indicate that 5HRE-CBDhVEGF lentiviral vector system could improve cardiac function in the collagen-targeting and hypoxia-inducible manners.
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影响因子：
5.1
作者：
Shibata, T;Giaccia, AJ;Brown, JM
通讯作者：
Brown, JM
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39.3
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LAURENT, GJ
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Maguire, Albert M.;High, Katherine A.;Auricchio, Alberta;Wright, J. Fraser;Pierce, Eric A.;Testa, Francesco;Mingozzi, Federico;Bennicelli, Jeannette L.;Ying, Gui-shuang;Rossi, Settimio;Fulton, Ann;Marshall, Kathleen A.;Banfi, Sandra;Chung, Daniel C.;Morgan, Jessica I. W.;Hauck, Bernd;Zelenaia, Olga;Zhu, Xiaosong;Raffini, Leslie;Coppieters, Frauke;De Baere, Elfride;Shindler, Kenneth S.;Volpe, Nicholas J.;Surace, Enrico M.;Acerra, Carmela;Lyubarsky, Arkady;Redmond, T. Michael;Stone, Edwin;Sun, Junwei;McDonnell, Jennifer Wellman;Leroy, Bart P.;Simonelli, Francesca;Bennett, Jean
通讯作者：
Bennett, Jean