Novel Insights into the Cardio-Protective Effects of FGF21 in Lean and Obese Rat Hearts

Vanlata Patel,Harpal S Randeva,Raghu Adya,Edward W Hillhouse,Bee K Tan,Sunil K Bhudia,Jing Chen,Muhammad F Bari,Manjunath Ramanjaneya,Emilio Hirsch

doi:10.1371/journal.pone.0087102

Abstract

AimsFibroblast 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 ResultsFGF21, 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.ConclusionIn 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.

Highlights

The pandemic of obesity is associated with a critical increase in atherosclerotic cardiovascular disease (CVD) that is one of the leading causes of global mortality and morbidity [1], ; atheromatous growth in the vascular wall causes life-threatening myocardial infarction (MI) [2]
In an ex vivo Langendorff system, we show that Fibroblast growth factor 21 (FGF21) induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity
Immunocyto/histochemistry and confocal analysis [Fig. 2B] showed intracellular FGF21 staining in adult rat cardiomyocyte [B1] and [B2] rat heart

Summary

Introduction

The pandemic of obesity is associated with a critical increase in atherosclerotic cardiovascular disease (CVD) that is one of the leading causes of global mortality and morbidity [1], ; atheromatous growth in the vascular wall causes life-threatening myocardial infarction (MI) [2]. Impairment of cardiac function following MI activates innate protective mechanisms that limit myocardial injury and promote repair [3]. These include increased production of cardiomyocyte survival factors from distant organs such as the liver and adipose tissue [4,5]. The fibroblast growth factor (FGF) family is abundantly expressed in the liver and white adipose tissue (WAT) regulating multiple physiological functions including growth, development, angiogenesis and wound healing [8,9]. No study has shown the direct involvement of FGF21 in obesity related CVD. We sought to elucidate the role of FGF21 in mediating myocardial protection following MI within this context

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Results

Conclusion