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
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
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DOI：
10.1093/cvr/cvx165
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发表时间：
2017-11-01
影响因子：
10.8
通讯作者：
Schultz, Jo El J.
中科院分区：
文献类型：
--
作者：
Huang, Chahua;Liu, Yang;Schultz, Jo El J.
目的成纤维细胞生长因子1（Fibroblast growth factor 1，FGF 1）是一种肝素/硫酸乙酰肝素结合生长因子，是一种有效的心肌保护剂。然而，肝素（进入急诊室的MI患者的护理标准）对FGF 1的心脏保护作用的影响尚不清楚。采用大鼠心肌梗死模型，比较心肌保护电位（降低梗死面积和改善缺血后功能）的天然FGF 1和工程化FGF 1在不存在或存在肝素的情况下，在再灌注开始时给予具有降低的肝素结合亲和力的FGF 1（Delta HBS））。FGF 1和FGF 1（Delta HBS）不改变肝素的抗凝特性。与生理盐水相比，单独用肝素或天然FGF 1治疗显著减小了梗死面积（P < 0.05）。令人惊讶的是，与FGF 1相比，用FGF 1（Delta HBS）治疗显著降低了梗死面积（P < 0.05）。天然和修饰的FGF 1均恢复收缩和舒张功能（与盐水或肝素相比P < 0.05）。此外，与FGF 1相比，FGF 1（Delta HBS）对心脏功能的改善作用更大（P < 0.05）。肝素对FGF 1的心脏保护作用（梗死面积、缺血后功能恢复）有负面影响（P < 0.05），但对FGF 1无影响（Delta HBS）。肝素还减少了FGF 1（但不是FGF 1（Δ HBS））向左心室的生物分布。FGF 1和FGF 1（δ HBS）结合并触发FGFR 1诱导的ERK 1/2下游活化（P < 0.05）;然而，肝素联合治疗降低了FGF 1产生的ERK 1/2激活，但对FGF 1激活的ERK 1/2激活无影响。结论对FGF 1的肝素结合区进行修饰，即使在肝素存在的情况下，也能显著提高心脏保护效果，鉴定可用于缺血性心脏病治疗用途的新型FGF配体。
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 (FGF1(Delta HBS)) with reduced heparin-binding affinity when given at the onset of reperfusion in the absence or presence of heparin. FGF1 and FGF1(Delta HBS) 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 FGF1(Delta HBS) 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, FGF1(Delta HBS) 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 FGF1(Delta HBS). Heparin also reduced the biodistribution of FGF1, but not FGF1(Delta HBS), to the left ventricle. FGF1 and FGF1(Delta HBS) 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 FGF1(Delta HBS).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.