A novel fibroblast growth factor-1 ligand with reduced heparin binding protects the heart against ischemia-reperfusion injury in the presence of heparin co-administration

Abstract

Aims Fibroblast growth factor 1 (FGF1), a heparin/heparan sulfate-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. Methods and results To address this, a rat model of MI was employed to compare cardioprotective potentials (lower infarct size and improve post-ischemic function) 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. FGF1 and FGF1ΔHBS did not alter heparin's anticoagulant properties. Treatment with heparin alone or native FGF1 significantly reduced infarct size compared to saline (P<0.05). Surprisingly, treatment with FGF1ΔHBS markedly lowered infarct size compared to FGF1 (P<0.05). Both native and modified FGF1 restored contractile and relaxation function (P<0.05 versus saline or heparin). Furthermore, FGF1ΔHBS had greater improvement in cardiac function compared to FGF1 (P<0.05). Heparin negatively impacted the cardioprotective effects (infarct size, post-ischemic recovery of function) of FGF1 (P<0.05) but not of FGF1ΔHBS. Heparin also reduced the biodistribution of FGF1, but not FGF1ΔHBS, to the left ventricle. FGF1 and FGF1ΔHBS bound and triggered FGFR1-induced downstream activation of ERK1/2 (P<0.05); yet, heparin co-treatment decreased FGF1-produced ERK1/2 activation, but not that activated by FGF1ΔHBS. Conclusion 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.