Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function

Xiaoli Liu, Alok S. Pachori, Christopher A. Ward, J. Paul Davis, Massimiliano Gnecchi, Deling Kong, Lunan Zhang, Jared Murduck, Shaw Fang Yet, Mark A. Perrella, Richard E. Pratt, Victor J. Dzau, Luis G. Melo

Research output: Contribution to journalArticlepeer-review

Abstract

We reported previously that predelivery of the anti-oxidant gene heme oxygenase-1 (HO-1) to the heart by adeno associated virus (AAV) markedly reduces injury after acute myocardial infarction (MI). However, the effect of HO-1 gene delivery on postinfarction recovery has not been investigated. In the current study, we assessed the effect of HO-1 gene delivery on post-MI left ventricle (LV) remodeling and function using echocardiographic imaging and histomorphometric approaches. Two groups of Sprague-Dawley rats were injected with 4 × 1011 particles of AAV-LacZ (control) or AAV-hHO-1 in the LV wall. Eight wk after gene transfer, the animals were subjected to 30 min of ischemia by ligation of left anterior descending artery (LAD) followed by reperfusion. Echocardiographic measurements were obtained in a blinded fashion prior and at 1.5 and 3 months after I/R. Ejection fraction (EF) was reduced by 13% and 40% in the HO-1 and LacZ groups, respectively at 1.5 months after MI. Three months after MI, EF recovered fully in the HO-1, but only partially in the LacZ-treated animals. Post-MI LV dimensions were markedly increased and the anterior wall was markedly thinned in the LacZ-treated animals compared with the HO-1-treated animals. Significant myocardial scarring and fibrosis were observed in the LacZ-group in association with elevated levels of interstitial collagen I and III and MMP-2 activity. Post-MI myofibroblast accumulation was reduced in the HO-1-treated animals, and retroviral overexpression of HO-1 reduced proliferation of isolated cardiac fibroblasts. Our data indicate that rAAV-HO-1 gene transfer markedly reduces fibrosis and ventricular remodeling and restores LV function and chamber dimensions after myocardial infarction.

Original languageEnglish
Pages (from-to)207-216
Number of pages10
JournalFASEB Journal
Volume20
Issue number2
DOIs
Publication statusPublished - Feb 2006

Keywords

  • Echocardiography
  • Gene therapy
  • Ischemia
  • Myocardial infarction
  • Reperfusion
  • Viruses

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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