title: Gene transfer as a strategy to achieve permanent cardioprotection II: rAAV-mediated gene therapy with heme oxygenase-1 limits infarct size 1 year later without adverse functional consequences.
abstract: Extensive evidence indicates that heme oxygenase-1 (HO-1) exerts potent cytoprotective effects in response to stress. Previous studies have shown that gene therapy with HO-1 protects against myocardial ischemia/reperfusion injury for up to 8 weeks after gene transfer. However, the long-term effects of HO-1 gene therapy on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the HO-1 gene (rAAV/HO-1) that enables long-lasting transgene expression. Mice received injections in the anterior LV wall of rAAV/LacZ (LacZ group) or rAAV/HO-1 (HO-1 group); 1 year later, they were subjected to a 30-min coronary occlusion (O) and 4 h of reperfusion (R). Cardiac HO-1 gene expression was confirmed at 1 month and 1 year after gene transfer by immunoblotting and immunohistochemistry analyses. In the HO-1 group, infarct size (% of risk region) was dramatically reduced at 1 year after gene transfer (11.2 ± 2.1%, n = 12, vs. 44.7 ± 3.6%, n = 8, in the LacZ group; P < 0.05). The infarct-sparing effects of HO-1 gene therapy at 1 year were as powerful as those observed 24 h after ischemic PC (six 4-min O/4-min R cycles) (15.0 ± 1.7%, n = 10). There were no appreciable changes in LV fractional shortening, LV ejection fraction, or LV end-diastolic or end-systolic diameter at 1 year after HO-1 gene transfer as compared to the age-matched controls or with the LacZ group. Histology showed no inflammation in the myocardium 1 year after rAAV/HO-1-mediated gene transfer. These results demonstrate, for the first time, that rAAV-mediated HO-1 gene transfer confers long-term (1 year), possibly permanent, cardioprotection without adverse functional consequences, providing proof of principle for the concept of achieving prophylactic cardioprotection (i.e., "immunization against infarction").
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, 550 S. Jackson Street, Louisville, KY 40292, USA.
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Li
authors.forename: Yiru
authors.initials: Y
authors.lastname: Guo
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Ou
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Wu
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: Fangping
authors.initials: F
authors.lastname: Yuan
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Hunt
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D052247:Nitric Oxide Synthase Type II