Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
Vanlata
V
Patel
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
Raghu
R
Adya
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
Jing
J
Chen
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
Manjunath
M
Ramanjaneya
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom ; Department of Pathology, Dow International Medical College, Karachi, Pakistan.
Muhammad F
MF
Bari
Department of Cardiothoracic Surgery, UHCW NHS Trust, Coventry, United Kingdom.
Sunil K
SK
Bhudia
Hamad Medical Corporation & Weill Cornell Medical School, Doha, Qatar.
Edward W
EW
Hillhouse
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
Bee K
BK
Tan
Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
Harpal S
HS
Randeva
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018613:Microscopy, Confocal; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D020011:Protective Agents / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D020011:Protective Agents; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases