Published Online
on February 23, 2004

A more recent version of this article appeared on April 1, 2004

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Submitted on November 7, 2003
Revised on November 20, 2003

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

Yao Liang Tang; Yi Tang; Y. Clare Zhang; Keping Qian; Leping Shen; and M. Ian Phillips^*

From the Department of Pediatrics, College of Medicine and All Children’s Hospital Research Institute (Y.L.T., Y.C.Z., K.Q., L.S., M.I.P.), University of South Florida, St. Petersburg, Fla; and Department of Medicine (Y.T.), Stanford University, Stanford, Calif.

^* To whom correspondence should be addressed. E-mail: iphillips{at}research.usf.edu.

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-. 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.

Key words: ischemia • genes • heart

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