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PRECLINICAL STUDY

Chronic Recurrent Myocardial Ischemic Injury Is Significantly Attenuated by Pre-Emptive Adeno-Associated Virus Heme Oxygenase-1 Gene Delivery

Alok S. Pachori, PhD^_*, Luis G. Melo, PhD, Lunan Zhang, MD^_*, Scott D. Solomon, MD and Victor J. Dzau, MD^_*,_*

^_* Department of Medicine, Duke University Medical Center, Durham, North Carolina
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Department of Physiology, Queen’s University, Kingston, Ontario, Canada

Manuscript received June 22, 2005; revised manuscript received August 23, 2005, accepted September 13, 2005.

^_* Reprint requests and correspondence: Dr. Victor J. Dzau, Office of the Chancellor, DUMC 3701, Durham, North Carolina 27710 (Email: victor.dzau{at}duke.edu).

OBJECTIVES: We assessed the hypothesis that overexpression of the antioxidant enzyme heme oxygenase (HO)-1 may protect against chronic recurrent ischemia/reperfusion injury.

BACKGROUND: Multiple and recurring episodes of myocardial ischemia can result in significant myocardial damage, including myocyte death, fibrosis, and wall thinning, leading to impaired ventricular function and cardiac failure.

METHODS: In this study we used a closed-chest rodent model of chronic recurring myocardial ischemia and reperfusion to investigate the efficacy of pre-emptive gene therapy in overexpressing the antioxidant enzyme HO-1, using adeno-associated virus (AAV)-2 as the delivery vector.

RESULTS: We show that constitutive overexpression of HO-1 can prevent myocardial wall thinning, inflammation, fibrosis, and deterioration of cardiac function (as measured by echocardiography, histology, and immunohistochemistry) induced by repeated transient myocardial ischemia and reperfusion injury. With HO-1 therapy, there was a significant reduction in apoptosis as determined by levels of markers of survival proteins and terminal deoxynucleotidyltransferase dUTP nick end-labeling staining. This prevention of tissue damage was also associated with reduction in superoxide generation.

CONCLUSIONS: Taken together we provide the first evidence of the therapeutic efficacy of pre-emptive AAV–HO-1 delivery for prevention against multiple ischemic injury. This approach protects myocytes by simultaneously activating protective response and inhibiting pathological left ventricular remodeling and, therefore, may be a useful cardio-protective strategy for patients with coronary artery disease at a high risk for recurrent myocardial ischemia.

Abbreviations and Acronyms   AAV = adeno-associated virus   ANOVA = analysis of variance   DHE = dihydroethidium   ECG = electrocardiogram   HO = heme oxygenase   I/R = ischemia and reperfusion   LAD = left anterior descending coronary artery   PBS = phosphate-buffered saline   RT-PCR = reverse transcriptase-polymerase chain reaction   SD = Sprague-Dawley   TUNEL = terminal deoxynucleotidyltransferase dUTP nick end-labeling

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