Abstract 19345: A Novel Fibroblast Growth Factor-1 Ligand With Reduced Heparin Binding Protects the Heart Against Ischemia-Reperfusion Injury in the Presence of Heparin Co-Treatment
Introduction: Fibroblast growth factor 1 (FGF1), a heparin/heparan sulfate (HS)-binding growth factor, is a potent cardioprotective agent against myocardial infarction (MI). The impact of heparin, the standard of care for MI patients entering the emergency room, on cardioprotective effects of FGF1 is unknown, however.
Hypothesis: The working hypothesis to be tested is that reduction of heparin-binding of FGF1 will enhance targeting to the heart and the cardioprotective efficacy of this newly engineered ligand.
Methods: To address this, a rat model of MI was employed to compare the cardioprotective potentials of native FGF1 and an engineered FGF1 (FGF1ΔHBS) with reduced heparin-binding affinity when given at the onset of reperfusion in the absence or presence of heparin. Hemodynamic parameters were measured by intracardiac catheter. Infarct size was determined by TTC staining. Blood clotting, FGF receptor (FGFR) activation and signaling as well as FGF biodistribution were also evaluated.
Results: Native FGF1 and FGF1ΔHBS did not influence the anticoagulant property of heparin. Treatment with heparin alone or native FGF1 significantly reduced the infarct size compared to saline (46±9% heparin, 35±9% native FGF1 versus 58±5% saline; p<0.05). Treatment with FGF1ΔHBS markedly reduced infarct size (22±6%) compared to native FGF1 (p<0.05). Both native and modified FGF1 restored contractile and relaxation function (p<0.05 versus saline and heparin group). Surprisingly, the modified FGF1 had greater improvement in cardiac function compared to native FGF1 (p<0.05). Heparin negatively impacted the cardioprotective effects (infarct size, post-ischemic recovery of function) of the native FGF1 (p<0.05) but not of the modified FGF1 (FGF1ΔHBS). Heparin reduced the biodistribution of native FGF1, but not FGF1ΔHBS, to the left ventricle. Finally, both native FGF1 and FGF1ΔHBS bound and triggered FGFR1-induced downstream activation of ERK1/2 (p<0.05).
Conclusions: These findings demonstrate that modification of the heparin-binding region of FGF1 significantly improves the cardioprotective efficacy, even in the presence of heparin, identifying a novel FGF ligand available for therapeutic use in ischemic heart disease.
Author Disclosures: C. Huang: None. A. Beenken: None. Y. Liu: None. M. Mohammadi: None. J.J. Schultz: None.
- © 2016 by American Heart Association, Inc.