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

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 LacZtreated 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 over‐expression 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.—Liu, X., Pachori, A. S., Ward, C. A., Davis, J. P., Gnecchi, M., Kong, D., Zhang, L., Murduck, J., Yet, S.‐F., Perrella, M. A., Pratt, R. E., Dzau, V. J., Melo, L. G. Heme oxygenase‐1 (HO‐1) inhibits postmyocardial infarct remodeling and restores ventricular function. FASEB J. 20, 207–216 (2006)

[1]  V. Choi,et al.  Production of Recombinant Adeno‐Associated Viral Vectors , 1999, Current protocols in human genetics.

[2]  Timothy D. Hanks,et al.  When is enough enough? , 2006, Nature Neuroscience.

[3]  Y. Okada,et al.  Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. , 2005, The Journal of clinical investigation.

[4]  N. Khaper,et al.  Inflammatory cytokines and postmyocardial infarction remodeling. , 2004, Circulation research.

[5]  M. Layne,et al.  Pre-emptive gene therapy using recombinant adeno-associated virus delivery of extracellular superoxide dismutase protects heart against ischemic reperfusion injury, improves ventricular function and prolongs survival , 2004, Gene Therapy.

[6]  R. Bolli,et al.  Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. , 2004, American journal of physiology. Heart and circulatory physiology.

[7]  C. Murry,et al.  Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair. , 2003, The American journal of pathology.

[8]  B. Jugdutt,et al.  Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? , 2003, Circulation.

[9]  Carl G. Figdor,et al.  Different Faces of the Heme-Heme Oxygenase System in Inflammation , 2003, Pharmacological Reviews.

[10]  A. Takeshita,et al.  Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. , 2003, American journal of physiology. Heart and circulatory physiology.

[11]  D. Holmes.  State of the art in coronary intervention. , 2003, The American journal of cardiology.

[12]  IchiroManabe,et al.  Gene Expression in Fibroblasts and Fibrosis , 2002 .

[13]  Ryozo Nagai,et al.  Gene Expression in Fibroblasts and Fibrosis: Involvement in Cardiac Hypertrophy , 2002, Circulation research.

[14]  F. Traganos,et al.  Differential effect of heme oxygenase-1 in endothelial and smooth muscle cell cycle progression. , 2002, Biochemical and biophysical research communications.

[15]  J. Oyama,et al.  Gene Therapy Strategy for Long-Term Myocardial Protection Using Adeno-Associated Virus-Mediated Delivery of Heme Oxygenase Gene , 2002, Circulation.

[16]  M. Entman,et al.  The inflammatory response in myocardial infarction. , 2002, Cardiovascular research.

[17]  E. Creemers,et al.  Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? , 2001, Circulation research.

[18]  James L. Park,et al.  Heme oxygenase-1 protects against vascular constriction and proliferation , 2001, Nature Medicine.

[19]  W. Colucci,et al.  Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. , 2001, American journal of physiology. Cell physiology.

[20]  A. Choi,et al.  Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway , 2000, Nature Medicine.

[21]  P. Sarathchandra,et al.  Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. , 2000, American journal of physiology. Heart and circulatory physiology.

[22]  L. Kobzik,et al.  Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. , 1999, The Journal of clinical investigation.

[23]  R. von Harsdorf,et al.  Superoxide induces apoptosis in cardiomyocytes, but proliferation and expression of transforming growth factor‐β1 in cardiac fibroblasts , 1999, FEBS letters.

[24]  B. Jugdutt,et al.  Rate of collagen deposition during healing and ventricular remodeling after myocardial infarction in rat and dog models. , 1996, Circulation.

[25]  N. Maulik,et al.  Induction of the haem oxygenase gene expression during the reperfusion of ischemic rat myocardium. , 1996, Journal of molecular and cellular cardiology.

[26]  M. Daemen,et al.  Collagen remodeling after myocardial infarction in the rat heart. , 1995, The American journal of pathology.

[27]  A. Kitabatake,et al.  Time Course of Functional Improvement in Stunned Myocardium in Risk Area in Patients With Reperfused Anterior Infarction , 1993, Circulation.

[28]  J. Eaton,et al.  Ferritin: a cytoprotective antioxidant strategem of endothelium. , 1992, The Journal of biological chemistry.

[29]  B. Ames,et al.  Bilirubin is an antioxidant of possible physiological importance. , 1987, Science.