Protection From Ischemic Heart Injury by a Vigilant Heme Oxygenase-1 Plasmid System

ABSTRACT—Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and...

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Bibliographic Details
Published in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 2004-04, Vol.43 (4), p.746-751
Main Authors: Tang, Yao Liang, Tang, Yi, Zhang, Y Clare, Qian, Keping, Shen, Leping, Phillips, M Ian
Format: Article
Language:English
Subjects:
Apoptosis - genetics
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Binding Sites
Biosensing Techniques
Caspase 3
Caspases - biosynthesis
Caspases - genetics
Cell Hypoxia - genetics
DNA-Binding Proteins
Endomyocardial Fibrosis - etiology
Endomyocardial Fibrosis - prevention & control
Gene Expression Regulation - genetics
Genes, Synthetic
Genetic Therapy
Genetic Vectors - genetics
Heme Oxygenase (Decyclizing) - biosynthesis
Heme Oxygenase (Decyclizing) - genetics
Heme Oxygenase (Decyclizing) - physiology
Heme Oxygenase-1
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Membrane Proteins - biosynthesis
Membrane Proteins - genetics
Myocardial Infarction - complications
Myocardial Infarction - enzymology
Myocardial Infarction - therapy
Myosin Light Chains - genetics
Plasmids - genetics
Protein Structure, Tertiary
Proto-Oncogene Proteins - biosynthesis
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-bcl-2 - biosynthesis
Regulatory Sequences, Nucleic Acid - genetics
Saccharomyces cerevisiae Proteins - genetics
TATA Box
Transcription Factors - chemistry
Transcription Factors - genetics
Transcriptional Activation
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Summary:ABSTRACT—Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-α. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0%±4.8% versus 62.5%±3.3%, P
ISSN:0194-911X
1524-4563
DOI:10.1161/01.HYP.0000120152.27263.87