Heme oxygenase-1 promotes neovascularization in ischemic heart by coinduction of VEGF and SDF-1.
Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with multiple protective functions in cardiovascular systems. Studies have shown that the timely cardiac HO-1 overexpression at acute phase of ischemic infarction (MI) provides protection via its anti-apoptotic and anti-inflammatory effects. Here we demonstrate that a delayed HO-1 transduction mediated by a recombinant adeno-associated virus in ischemic hearts of mice with permanent coronary artery ligation significantly attenuated left ventricular fibrosis and cardiac dysfunctions examined at 4 weeks post MI. HO-1-mediated protection was correlated with enhanced vascularization in the ischemic myocardium. HO-1 gene transfer resulted in a notable increase in the number of c-kit(+)- stem cells recruited to the infarcted area at 10 days after ligation. HO-1-mediated stem cell recruitment was also demonstrated in the heart of non-ischemic mice receiving intravenous infusion of green fluorescent protein-bearing bone marrow stem cells. Additional experiments revealed that vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were highly induced in HO-1 transduced myocardium. Mononuclear cell infiltration was evident and colocalized with angiogenic factors in the same region. Flow cytometry analysis of the mononuclear cells isolated from HO-1-transduced left ventricles revealed that over 50% of cells expressed CD34, a marker of hematopoietic stem cells and endothelial progenitor cells. VEGF and SDF-1 blockade by neutralizing antibodies significantly attenuated HO-1-mediated neovascularization and protection in infarcted mice. These data suggest that cardiac HO-1 gene transfer post MI provides protection at least in part by promoting neovascularization through inducing angiogenic factors and the recruitment of circulating progenitor/stem cells.
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC.
Heng-Huei
HH
Lin
Yen-Hui
YH
Chen
Pi-Fei
PF
Chang
Yi-Tsun
YT
Lee
Shaw-Fang
SF
Yet
Lee-Young
LY
Chau
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D000229:Dependovirus; D015316:Genetic Therapy; D006352:Heart Ventricles / Q000201:enzymology; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D009206:Myocardium / Q000201:enzymology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D018952:Antigens, CD34; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051547:Heme Oxygenase-1; D019009:Proto-Oncogene Proteins c-kit