Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.
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.
Pachori
Alok S
AS
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Melo
Luis G
LG
Hart
Melanie L
ML
Noiseux
Nicholas
N
Zhang
Lunan
L
Morello
Fulvio
F
Solomon
Scott D
SD
Stahl
Gregory L
GL
Pratt
Richard E
RE
Dzau
Victor J
VJ
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000276:immunology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D018482:Muscle, Skeletal / Q000201:enzymology / Q000293:injuries; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000628:therapy*
D016207:Cytokines; D008164:Luminescent Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1