Protection from ischemic heart injury by a vigilant heme oxygenase-1 plasmid system.
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.
Department of Pediatrics, College of Medicine and All Children's Hospital Research Institute, University of South Florida, St. Petersburg, Fla, USA.
Yao Liang
YL
Tang
Yi
Y
Tang
Y Clare
YC
Zhang
Keping
K
Qian
Leping
L
Shen
M Ian
MI
Phillips
D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D015374:Biosensing Techniques; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D004268:DNA-Binding Proteins; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000235:genetics*; D005813:Genes, Synthetic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051547:Heme Oxygenase-1; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000628:therapy*; D018994:Myosin Light Chains / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D016385:TATA Box; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D015533:Transcriptional Activation; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494772:BAK1 protein, human; C494826:BAX protein, human; D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D018994:Myosin Light Chains; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases