Patel Vanlata, Adya Raghu, Chen Jing, Ramanjaneya Manjunath, Bari Muhammad F, Bhudia Sunil K, Hillhouse Edward W, Tan Bee K, Randeva Harpal S
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom ; Department of Pathology, Dow International Medical College, Karachi, Pakistan.
PLoS One. 2014 Feb 3;9(2):e87102. doi: 10.1371/journal.pone.0087102. eCollection 2014.
Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia.
FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased.
In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia.
成纤维细胞生长因子21（FGF21）是一种具有多种作用的肝脏代谢调节因子。在肥胖和糖尿病（与心血管疾病发病率增加相关的状态）中，其血浆浓度会升高。因此，我们研究了FGF21对肥胖和正常体重心脏缺血时心脏保护的直接作用。
FGF21、FGF21受体1（FGFR1）和β-klotho（βKlotho）在啮齿动物、人类心脏和原代大鼠心肌细胞中表达。心脏FGF21以自分泌-旁分泌方式表达和分泌（实时逆转录聚合酶链反应/蛋白质免疫印迹法和酶联免疫吸附测定），对肥胖和缺氧作出反应，涉及FGFR1-βKlotho成分。心脏FGF21的表达和分泌在整体缺血时增加。相比之下，βKlotho在肥胖心脏中减少。在分离的成年大鼠心肌细胞中，FGF21激活了磷脂酰肌醇3激酶/蛋白激酶B（PI3K/Akt）、细胞外信号调节激酶1/2（ERK1/2）和腺苷酸活化蛋白激酶（AMPK）信号通路。在Langendorff灌注的大鼠（成年雄性野生型Wistar大鼠）心脏中，给予FGF21可在整体缺血后诱导显著的心脏保护和功能恢复。抑制PI3K/Akt、AMPK、ERK1/2和视黄酸受体α（ROR-α）信号通路会导致FGF21诱导的心脏保护和心脏功能恢复在整体缺血时显著降低。更重要的是，尽管心脏表达谱和循环FGF21水平升高，但肥胖时FGF21诱导的这种心脏保护反应减弱。
在离体Langendorff系统中，我们表明FGF21通过自分泌-旁分泌途径诱导心脏保护和心脏功能恢复，在肥胖时作用减弱。总的来说，我们的研究结果为FGF21在肥胖和缺血时诱导的心脏效应提供了新的见解。
