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 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-alpha. 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<0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-1 gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.

• Authors: Yao Liang Tang, Yi Tang, Y Clare Zhang, Keping Qian, Leping Shen, M Ian Phillips
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 43 Issue 4 Pg. 746-51 (Apr 2004) ISSN: 1524-4563 [Electronic] United States
• PMID: 14981066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BAK1 protein, human
• BAX protein, human
• DNA-Binding Proteins
• GAL4 protein, S cerevisiae
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Membrane Proteins
• Myosin Light Chains
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Saccharomyces cerevisiae Proteins
• Transcription Factors
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• HMOX1 protein, human
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• CASP3 protein, human
• Caspase 3
• Caspases

Topics

• Apoptosis (genetics)
• Binding Sites
• Biosensing Techniques
• Caspase 3
• Caspases (biosynthesis, genetics)
• Cell Hypoxia (genetics)
• DNA-Binding Proteins
• Endomyocardial Fibrosis (etiology, prevention & control)
• Gene Expression Regulation (genetics)
• Genes, Synthetic
• Genetic Therapy
• Genetic Vectors (genetics)
• Heme Oxygenase (Decyclizing) (biosynthesis, genetics, physiology)
• Heme Oxygenase-1
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit
• Membrane Proteins (biosynthesis, genetics)
• Myocardial Infarction (complications, enzymology, therapy)
• Myosin Light Chains (genetics)
• Plasmids (genetics)
• Protein Structure, Tertiary
• Proto-Oncogene Proteins (biosynthesis, genetics)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Regulatory Sequences, Nucleic Acid (genetics)
• Saccharomyces cerevisiae Proteins (genetics)
• TATA Box
• Transcription Factors (chemistry, genetics)
• Transcriptional Activation
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein