A Vigilant, Hypoxia-Regulated Heme Oxygenase-1 Gene Vector in the Heart Limits Cardiac Injury After Ischemia-Reperfusion In Vivo

• Published in: Journal of cardiovascular pharmacology and therapeutics 2005-12, Vol.10 (4), p.251-263
• Main Authors: Tang, Yao Liang, Qian, Keping, Zhang, Y. Clare, Shen, Leping, Phillips, M. Ian
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Gene Expression Regulation; Genetic Therapy; Genetic Vectors; Heme Oxygenase-1 - biosynthesis; Heme Oxygenase-1 - genetics; Humans; Hypoxia; Lipid Peroxidation; Male; Mice; Mice, Inbred BALB C; Myocardial Reperfusion Injury - prevention & control; Myocardial Reperfusion Injury - therapy; Myocardium - enzymology; Myocardium - metabolism; Plasmids; Ventricular Remodeling
• ISSN: 1074-2484; 1940-4034
• DOI: 10.1177/107424840501000405

Objectives: The effect of a cardiac specific, hypoxia-regulated, human heme oxygenase-1 (hHO-1) vector to provide cardioprotection from ischemia-reperfusion injury was assessed. Background: When myocardial ischemia and reperfusion is asymptomatic, the damaging effects are cumulative and patients miss timely treatment. A gene therapy approach that expresses therapeutic genes only when ischemia is experienced is a desirable strategy. We have developed a cardiac-specific, hypoxia-regulated gene therapy “vigilant vector” system that amplifies cardioprotective gene expression. Methods: Vigilant hHO-1 plasmids, LacZ plasmids, or saline (n = 40 per group) were injected into mouse heart 2 days in advance of ischemia-reperfusion injury. Animals were exposed to 60 minutes of ischemia followed by 24 hours of reperfusion. For that term (24 hours) effects, the protein levels of HO-1, inflammatory responses, apoptosis, and infarct size were determined. For long-term (3 week) effects, the left ventricular remodeling and recovery of cardiac function were assessed. Results: Ischemia-reperfusion resulted in a timely overexpression of HO-1 protein. Infarct size at 24 hours after ischemia-reperfusion was significantly reduced in the HO-1-treated animals compared with the LacZ-treated group or saline-treated group (P < .001). The reduction of infarct size was accompanied by a decrease in lipid peroxidant activity, inflammatory cell infiltration, and proapoptotic protein level in ischemia-reperfusion-injured myocardium. The long-term study demonstrated that timely, hypoxia-induced HO-1 overexpression is beneficial in conserving cardiac function and attenuating left ventricle remodelling. Conclusions: The vigilant HO-1 vector provides a protective therapy in the heart for reducing cellular damage during ischemia-reperfusion injury and preserving heart function.