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 construc...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2017-10-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-13547-1 |
| _version_ | 1819035982530347008 |
|---|---|
| author | Jing-Bo Xia Hai-Yan Wu Bing-Lin Lai Li Zheng Deng-Cheng Zhou Zao-Shang Chang Cheng-Zhou Mao Guang-Hui Liu Kyu-Sang Park Hui Zhao Soo-Ki Kim Guo-Hua Song Dong-Qing Cai Xu-Feng Qi |
| author_facet | Jing-Bo Xia Hai-Yan Wu Bing-Lin Lai Li Zheng Deng-Cheng Zhou Zao-Shang Chang Cheng-Zhou Mao Guang-Hui Liu Kyu-Sang Park Hui Zhao Soo-Ki Kim Guo-Hua Song Dong-Qing Cai Xu-Feng Qi |
| author_sort | Jing-Bo Xia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T07:58:17Z |
| format | Article |
| id | doaj.art-37551537bb7b421daf34ddb71884ba40 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-21T07:58:17Z |
| publishDate | 2017-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-37551537bb7b421daf34ddb71884ba402022-12-21T19:10:56ZengNature PortfolioScientific Reports2045-23222017-10-017111310.1038/s41598-017-13547-1Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarctionJing-Bo Xia0Hai-Yan Wu1Bing-Lin Lai2Li Zheng3Deng-Cheng Zhou4Zao-Shang Chang5Cheng-Zhou Mao6Guang-Hui Liu7Kyu-Sang Park8Hui Zhao9Soo-Ki Kim10Guo-Hua Song11Dong-Qing Cai12Xu-Feng Qi13Key Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityCollege of Environmental Science and Engineering, Guangdong University of TechnologyKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityDepartment of Physiology, Wonju College of Medicine, Yonsei UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong KongDepartment of Microbiology, Yonsei University Wonju College of MedicineInstitute of Atherosclerosis, TaiShan Medical UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityAbstract 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.https://doi.org/10.1038/s41598-017-13547-1 |
| spellingShingle | Jing-Bo Xia Hai-Yan Wu Bing-Lin Lai Li Zheng Deng-Cheng Zhou Zao-Shang Chang Cheng-Zhou Mao Guang-Hui Liu Kyu-Sang Park Hui Zhao Soo-Ki Kim Guo-Hua Song Dong-Qing Cai Xu-Feng Qi Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction Scientific Reports |
| title | Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction |
| title_full | Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction |
| title_fullStr | Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction |
| title_full_unstemmed | Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction |
| title_short | Gene delivery of hypoxia-inducible VEGF targeting collagen effectively improves cardiac function after myocardial infarction |
| title_sort | gene delivery of hypoxia inducible vegf targeting collagen effectively improves cardiac function after myocardial infarction |
| url | https://doi.org/10.1038/s41598-017-13547-1 |
| work_keys_str_mv | AT jingboxia genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT haiyanwu genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT binglinlai genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT lizheng genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT dengchengzhou genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT zaoshangchang genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT chengzhoumao genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT guanghuiliu genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT kyusangpark genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT huizhao genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT sookikim genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT guohuasong genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT dongqingcai genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction AT xufengqi genedeliveryofhypoxiainduciblevegftargetingcollageneffectivelyimprovescardiacfunctionaftermyocardialinfarction |