Basic Research in Cardiology

, Volume 106, Issue 6, pp 1367–1377

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

  • Qianhong Li
  • Yiru Guo
  • Qinghui Ou
  • Wen-Jian Wu
  • Ning Chen
  • Xiaoping Zhu
  • Wei Tan
  • Fangping Yuan
  • Buddhadeb Dawn
  • Li Luo
  • Gregory N. Hunt
  • Roberto Bolli
Original Contribution

DOI: 10.1007/s00395-011-0208-6

Cite this article as:
Li, Q., Guo, Y., Ou, Q. et al. Basic Res Cardiol (2011) 106: 1367. doi:10.1007/s00395-011-0208-6

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”).

Keywords

Heme oxygenase-1 Gene therapy Myocardial infarction Cardiac function Mouse 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Qianhong Li
    • 1
  • Yiru Guo
    • 1
  • Qinghui Ou
    • 1
  • Wen-Jian Wu
    • 1
  • Ning Chen
    • 1
  • Xiaoping Zhu
    • 1
  • Wei Tan
    • 1
  • Fangping Yuan
    • 1
  • Buddhadeb Dawn
    • 1
    • 3
  • Li Luo
    • 1
  • Gregory N. Hunt
    • 1
  • Roberto Bolli
    • 1
    • 2
  1. 1.Institute of Molecular CardiologyUniversity of LouisvilleLouisvilleUSA
  2. 2.Division of Cardiovascular MedicineUniversity of LouisvilleLouisvilleUSA
  3. 3.Cardiovascular Research InstituteUniversity of Kansas Medical CenterKansas CityUSA