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

2004; National Academy of Sciences; Volume: 101; Issue: 33 Linguagem: Inglês

10.1073/pnas.0404616101

1091-6490

Alok S. Pachori, Luis G. Melo, Melanie L. Hart, Nicolas Noiseux, Lunan Zhang, Fulvio Morello, Scott D. Solomon, Gregory L. Stahl, Richard E. Pratt, Victor J. Dzau,

Cardiac Arrest and Resuscitation

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.