Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene.
BACKGROUND
Ischemia and oxidative stress are the leading mechanisms for tissue injury. An ideal strategy for preventive/protective therapy would be to develop an approach that could confer long-term transgene expression and, consequently, tissue protection from repeated ischemia/reperfusion injury with a single administration of a therapeutic gene. In the present study, we used recombinant adeno-associated virus (rAAV) as a vector for direct delivery of the cytoprotective gene heme oxygenase-1 (HO-1) into the rat myocardium, with the purpose of evaluating this strategy as a therapeutic approach for long-term protection from ischemia-induced myocardial injury.


RESULTS
Human HO-1 gene (hHO-1) was delivered to normal rat hearts by intramyocardial injection. AAV-mediated transfer of the hHO-1 gene 8 weeks before acute coronary artery ligation and release led to a dramatic reduction (>75%) in left ventricular myocardial infarction. The reduction in infarct size was accompanied by decreases in myocardial lipid peroxidation and in proapoptotic Bax and proinflammatory interleukin-1beta protein abundance, concomitant with an increase in antiapoptotic Bcl-2 protein level. This suggested that the transgene exerts its cardioprotective effects in part by reducing oxidative stress and associated inflammation and apoptotic cell death.


CONCLUSIONS
This study documents the beneficial therapeutic effect of rAAV-mediated transfer, before myocardial injury, of a cytoprotective gene that confers long-term myocardial protection from ischemia/reperfusion injury. Our data suggest that this novel "pre-event" gene transfer approach may provide sustained tissue protection from future repeated episodes of injury and may be beneficial as preventive therapy for patients with or at risk of developing coronary ischemic events.
Melo
Luis G
LG
Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
Agrawal
Reitu
R
Zhang
Lunan
L
Rezvani
Mojgan
M
Mangi
Abeel A
AA
Ehsan
Afshin
A
Griese
Daniel P
DP
Dell'Acqua
Giorgio
G
Mann
Michael J
MJ
Oyama
Junichi
J
Yet
Shaw-Fang
SF
Layne
Matthew D
MD
Perrella
Mark A
MA
Dzau
Victor J
VJ
D000818:Animals; D017209:Apoptosis; D003331:Coronary Vessels; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1; D006801:Humans; D008026:Ligation; D008297:Male; D008565:Membrane Proteins; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013995:Time; D019076:Transgenes / Q000235:genetics
D016207:Cytokines; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1