Cardiac-Specific Expression of the Hepatocyte Growth Factor (HGF) Under the Control of a TnIc Promoter Confers a Heart Protective Effect After Myocardial Infarction (MI)
Zhihui Xu, Zhengxian Tao, Zhuowen Xu, Yuefeng Yang, Hua Wang, Lisheng Wang, Zuze Wu, Qi Tan, Ningtian Zhou, Ming Zhang, Pengsheng Chen and Zhijian Yang
Affiliation: Department of Cardiology and Department of Geriatrics, The First affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
Keywords: Troponin, promoter, HGF, luciferase.
Objective: Uncontrolled therapeutic gene expression and neovascularization in non-specific tissues has lowered
the safety of gene therapy. The aim of the study was to identify a cardiac-specific promoter to control target gene expression
in heart tissue in vitro and in vivo. Methods: Adenovirus vectors containing the firefly luciferase or hepatocyte
growth factor (HGF) genes under control of the Troponin I (TnIc) or Cytomegalievirus (CMV) promoters were transfected
into cell lines or injected into the left ventricular wall of Sprague Dawley (SD) rats via thoracotomy. Myocardial infarction
(MI) was induced immediately before direct injection. In vivo luciferase expression was assessed using a bioluminescence
imaging system. Heart function was monitored via echocardiograph intermittently for eight weeks after injection.
Results: The constitutively active CMV promoter yielded luciferase expression throughout the body while luciferase
expression driven by the TnIc promoter was largely restricted to the hypoxic heart. The CMV promoter was more efficient,
yielding 100-1000 fold more light output than the TnIc promoter. Four weeks after injection, we observed a significant
decline in the ejection fraction (EF) in saline and Ad-Null groups but a 17% increase in the Ad-CMV-HGF group. No
change in EF was observed in the Ad-TnIc-HGF group. Conclusions: The adenovirus vector combined with the TnIc
promoter largely restricts gene-targeted therapy in the hypoxic heart and prevents heart failure after myocardial infarction.
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