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Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts Patel V; Adya R; Chen J; Ramanjaneya M; Bari MF; Bhudia SK; Hillhouse EW; Tan BK; Randeva HSPLoS One 2014[]; 9 (2): e87102AIMS: 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. METHODS AND RESULTS: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (betaKlotho) 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-betaKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast betaKlotho 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-alpha (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. CONCLUSION: 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.|AMP-Activated Protein Kinases/metabolism[MESH]|Animals[MESH]|Blotting, Western[MESH]|Cells, Cultured[MESH]|Extracellular Signal-Regulated MAP Kinases/metabolism[MESH]|Fibroblast Growth Factors/genetics/*metabolism/pharmacology[MESH]|Gene Expression[MESH]|Heart/drug effects/physiopathology[MESH]|Humans[MESH]|In Vitro Techniques[MESH]|Male[MESH]|Microscopy, Confocal[MESH]|Myocardial Ischemia/genetics/*metabolism[MESH]|Myocardium/*metabolism/pathology[MESH]|Myocytes, Cardiac/drug effects/metabolism[MESH]|Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism[MESH]|Obesity/genetics/*metabolism[MESH]|Phosphatidylinositol 3-Kinase/metabolism[MESH]|Protective Agents/metabolism/pharmacology[MESH]|Proto-Oncogene Proteins c-akt/metabolism[MESH]|Rats[MESH]|Rats, Wistar[MESH]|Reverse Transcriptase Polymerase Chain Reaction[MESH]|Signal Transduction/drug effects[MESH] |
