title: Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway.
abstract: OBJECTIVE
  This study investigated fibroblast growth factor 21 (FGF21)-mediated cardiac protection against apoptosis caused by diabetic lipotoxicity and explored the protective mechanisms involved.
  
  
  METHODS
  Cardiac Fgf21 mRNA expression was examined in a diabetic mouse model using real-time PCR. After pre-incubation of palmitate-treated cardiac H9c2 cells and primary cardiomyocytes with FGF21 for 15 h, apoptosis and Fgf21-induced cell-survival signalling were investigated using small interfering (si)RNA and/or pharmacological inhibitors. We also examined the cardiac apoptotic signalling and structural and functional indices in wild-type and Fgf21-knockout (Fgf21-KO) diabetic mice.
  
  
  RESULTS
  In a mouse model of type 1 diabetes, cardiac Fgf21 expression was upregulated about 40-fold at 2 months and 3-1.5-fold at 4 and 6 months after diabetes. FGF21 significantly reduced palmitate-induced cardiac apoptosis. Mechanistically, palmitate downregulated, but FGF21 upregulated, phosphorylation levels of extracellular signal-regulated kinase (ERK)1/2, mitogen-activated protein kinase 14 (p38 MAPK) and AMP-activated protein kinase (AMPK). Inhibition of each kinase with its inhibitor and/or siRNA revealed that FGF21 prevents palmitate-induced cardiac apoptosis via upregulating the ERK1/2-dependent p38 MAPK-AMPK signalling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic or fatty-acid-infused mice significantly prevented cardiac apoptosis and reduced inactivation of ERK1/2, p38 MAPK and AMPK and prevented cardiac remodelling and dysfunction. The Fgf21-KO mice were more susceptible to diabetes-induced cardiac apoptosis, and this could be prevented by administration of FGF21. Deletion of Fgf21 did not further exacerbate cardiac dysfunction.
  
  
  CONCLUSIONS
  These results demonstrate that FGF21 prevents lipid- or diabetes-induced cardiac apoptosis by activating the ERK1/2-p38 MAPK-AMPK pathway. FGF21 may be a therapeutic target for the treatment of diabetes-related cardiac damage.
authors.affiliation: Chinese-American Research Institute for Diabetic Complication, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan University-Town, Wenzhou, 325035, People's Republic of China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Huang
authors.forename: Junlian
authors.initials: J
authors.lastname: Gu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yan
authors.forename: Xuemian
authors.initials: X
authors.lastname: Lu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.forename: Minglong
authors.initials: M
authors.lastname: Shao
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors