Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

doi:10.1073/pnas.0404616101

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

^*Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; ^†Department of Physiology, Queen's University, Kingston, ON, Canada K7L 3N6; and ^‡Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115

Communicated by Eugene Braunwald, Partners HealthCare System, Inc., Boston, MA, June 29, 2004 (received for review April 16, 2004)

Abstract

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

Footnotes

↵ § To whom correspondence should be sent at the present address: Office of the Chancellor, Duke University Medical Center 3701, Durham, NC 27710. E-mail: victor.dzau{at}duke.edu.
Abbreviations: I/R, ischemia and reperfusion; HO-1, heme-oxygenase-1; hHO-1, human HO-1; AAV, adenoassociated vector; HRE, hypoxia response element.