N009 Enhancement of Sonic Hedgehog-induced cardiac functional recovery is augmented by CXCR4 antagonist via MMP-9-dependent pathway after myocardial infarction - 17/04/09
Résumé |
Background |
We have shown that the Sonic Hedgehog (Shh) embryonic signalling pathway can be reactivated in myocardial infarction (MI) in adults inducing expression of pro-angiogenic factors. We hypothesized that combining Shh gene therapy and endothelial BM-derived pro-angiogenic cell mobilization by a CXCR4 antagonist, AMD3100 (AMD), could exert synergistic effects and would be superior to either single strategy for the treatment of MI.
Methods and Results |
In vitro, human Shh plasmid activates the Hedgehog pathway and induces transcription and secretion of VEGF and SDF-1 from fibroblasts. Shh conditioned medium from these fibroblasts promotes capillary morphogenesis, proliferation and migration. In vivo, MI was induced in WT and GFP-bone marrow (BM) transplanted mice randomly assigned in 4 treatment groups: control ; AMD (single dose, 5mg/kg s.c.); Shh (intramyocardial administration of 100μg Shh plasmid DNA at time of MI surgery); AMD+Shh group. Left ventricular ejection fraction (LVEF) was evaluated by echo up to 4 weeks post MI. AMD+Shh group exhibited the best LV function (control: 28+/-3 % ; AMD: 36+/-2 % ; Shh: 40+/-3 % ; AMD+Shh: 48+/-2 % ; P<0.05 AMD+Shh vs. other groups). Furthermore, combination of AMD with sub-therapeutic dose of Shh resulted in a significant improvement of cardiac function recovery compared to monotherapy, highlighting its synergistic effect (P<0.05). Elastic staining and immunohistological analyses demonstrated reduced infarct size and increased capillary density in the AMD+Shh group (both P<0.05). Combination therapy was also associated with significant increase in number of GFP-BS lectin BM-derived cells incorporated into the ischemic area (P<0.05).
We then explored the certain potential mechanisms of the favourable effects of combination therapy. MMP-9 mRNA expression was increased in ischemic myocardium in the AMD+Shh (10-fold versus control). The positive effect on EF of combined treatment was attenuated in MMP-9 KO mice (WT mice 49+/-2 % vs. KO mice 36+/-4 % ; P<0.05), suggesting that MMP-9 might be a key modulator of the combination therapy.
Conclusion |
Pharmacological enhancement of Shh gene therapy via BM-cell mobilization by a CXCR4 antagonist is mediated via an MMP-9-dependent pathway. The combination may offer advantages in safety and feasibility by allowing lower dose gene transfer while improving outcomepost-MI
Le texte complet de cet article est disponible en PDF.Vol 102 - N° S1
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