Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction

Jing Bo Xia, Hai Yan Wu, Bing Lin Lai, Li Zheng, Deng Cheng Zhou, Zao Shang Chang, Cheng Zhou Mao, Guang Hui Liu, Kyusang Park, Hui Zhao, Soo-Ki Kim, Guo Hua Song, Dong Qing Cai, Xu Feng Qi

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Abstract

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.

Original languageEnglish
Article number13273
JournalScientific reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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Vascular Endothelial Growth Factor A
Lentivirus
Collagen
Myocardial Infarction
Cytomegalovirus
Myocardium
Genes
Human Umbilical Vein Endothelial Cells
Collagen Type I
Safety
Injections
Hypoxia
Proteins
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Cite this

Xia, Jing Bo ; Wu, Hai Yan ; Lai, Bing Lin ; Zheng, Li ; Zhou, Deng Cheng ; Chang, Zao Shang ; Mao, Cheng Zhou ; Liu, Guang Hui ; Park, Kyusang ; Zhao, Hui ; Kim, Soo-Ki ; Song, Guo Hua ; Cai, Dong Qing ; Qi, Xu Feng. / Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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title = "Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction",
abstract = "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.",
author = "Xia, {Jing Bo} and Wu, {Hai Yan} and Lai, {Bing Lin} and Li Zheng and Zhou, {Deng Cheng} and Chang, {Zao Shang} and Mao, {Cheng Zhou} and Liu, {Guang Hui} and Kyusang Park and Hui Zhao and Soo-Ki Kim and Song, {Guo Hua} and Cai, {Dong Qing} and Qi, {Xu Feng}",
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Xia, JB, Wu, HY, Lai, BL, Zheng, L, Zhou, DC, Chang, ZS, Mao, CZ, Liu, GH, Park, K, Zhao, H, Kim, S-K, Song, GH, Cai, DQ & Qi, XF 2017, 'Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction', Scientific reports, vol. 7, no. 1, 13273. https://doi.org/10.1038/s41598-017-13547-1

Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction. / Xia, Jing Bo; Wu, Hai Yan; Lai, Bing Lin; Zheng, Li; Zhou, Deng Cheng; Chang, Zao Shang; Mao, Cheng Zhou; Liu, Guang Hui; Park, Kyusang; Zhao, Hui; Kim, Soo-Ki; Song, Guo Hua; Cai, Dong Qing; Qi, Xu Feng.

In: Scientific reports, Vol. 7, No. 1, 13273, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Xia, Jing Bo

AU - Wu, Hai Yan

AU - Lai, Bing Lin

AU - Zheng, Li

AU - Zhou, Deng Cheng

AU - Chang, Zao Shang

AU - Mao, Cheng Zhou

AU - Liu, Guang Hui

AU - Park, Kyusang

AU - Zhao, Hui

AU - Kim, Soo-Ki

AU - Song, Guo Hua

AU - Cai, Dong Qing

AU - Qi, Xu Feng

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