Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Avda Diagonal 643, Barcelona 08028, Spain
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Avda Diagonal 643, Barcelona 08028, Spain.
Cardiovasc Res. 2015 Apr 1;106(1):19-31. doi: 10.1093/cvr/cvu263. Epub 2014 Dec 23.
Oxidative stress mediated by reactive oxygen species (ROS) plays a striking role in the pathogenesis of heart failure, and antioxidants have been shown to attenuate cardiac remodelling in experimental models of cardiac damage. We recently showed that fibroblast growth factor 21 (Fgf21) is produced by the heart and exerts protective effects, preventing cardiac hypertrophy development. The aim of the study was to determine the effects of Fgf21 during oxidative stress signalling in the heart.
Fgf21 treatment in cardiomyocytes in culture induced the expression of genes encoding proteins involved in antioxidative pathways, including mitochondrial uncoupling proteins (Ucp2 and Ucp3) and superoxide dismutase-2 (Sod2) and reduced ROS production. In keeping with this, expression of antioxidant genes in response to lipopolysaccharide (LPS)-induced stimulation of pro-inflammatory pathways or isoproterenol-induced cardiac hypertrophy in the heart was reduced in Fgf21-null mice. Moreover, we found that Fgf21 is expressed in and released by cardiomyocytes in response to LPS, and its expression is under the control of the Sirt1 (sirtuin-1) pathway. This Fgf21 released by cardiomyocytes acts in an autocrine manner to protect cells against oxidative stress. Finally, failing human hearts showed up-regulation of Fgf21, Ucp3, and Sod2, confirming the association between Fgf21 induction and the control of cardiac oxidative stress pathways.
Our data indicate that Fgf21 regulates genes involved in antioxidant pathways in an autocrine manner, thus preventing ROS production in cardiac cells. Therefore, Fgf21 acts as an antioxidant factor in the heart, preventing induction of pro-oxidative pathways by inflammatory or hypertrophic conditions.
活性氧（ROS）介导的氧化应激在心力衰竭的发病机制中起着重要作用，抗氧化剂已被证明可减轻心脏损伤的实验模型中的心脏重构。我们最近表明，成纤维细胞生长因子 21（Fgf21）由心脏产生并发挥保护作用，可防止心脏肥大的发展。本研究的目的是确定 Fgf21 在心脏氧化应激信号传导中的作用。
在培养的心肌细胞中，Fgf21 处理诱导编码抗氧化途径蛋白的基因表达，包括线粒体解偶联蛋白（Ucp2 和 Ucp3）和超氧化物歧化酶-2（Sod2），并减少 ROS 的产生。与此一致的是，在 Fgf21 缺失小鼠中，LPS 诱导的促炎途径或异丙肾上腺素诱导的心脏肥大刺激下，抗氧化基因的表达减少。此外，我们发现 Fgf21 在 LPS 刺激下在心肌细胞中表达并释放，其表达受 Sirt1（沉默调节蛋白-1）途径的控制。这种由心肌细胞释放的 Fgf21 以自分泌方式作用，可保护细胞免受氧化应激。最后，衰竭的人心肌中 Fgf21、Ucp3 和 Sod2 的表达上调，证实了 Fgf21 诱导与心脏氧化应激途径控制之间的关联。
我们的数据表明，Fgf21 以自分泌方式调节抗氧化途径中的基因，从而防止心脏细胞中 ROS 的产生。因此，Fgf21 作为心脏中的抗氧化因子，可防止炎症或肥大条件下诱导的促氧化途径。
