Abstract 16139: Fgf21 Expresses in Diabetic Hearts and Protects from Palmitate- and Diabetes-Induced Cardiac Cell Death In Vitro and In Vivo Via Erk1/2-Dependent P38 Mapk/ampk Signaling Pathways
The present study examined whether fibroblast growth factor (FGF) 21 mRNA expresses in the heart of diabetic mice and also protects from fatty acid (palmitate)- and diabetes-induced cardiac cell death. Type 1 diabetes, induced by streptozotocin (STZ), up-regulated FGF21 expression about 40 folds at 2 months and 3 - 1.5 folds at 4 and 6 months of diabetes. To define if the up-regulated cardiac FGF21 expression offers a protective effect on fatty acid- or diabetes-induced cardiac damage, H9C2 cells were exposed to palmitate at 62.5 nM for 15 h, which induced significant apoptosis, examined by DNA fragmentation and cleaved caspase-3. Pre-incubation of palmitate-treated cells with FGF21 significantly reduced the apoptosis. Mechanistically palmitate down-regulated, and FGF21 up-regulated, phosphorylation levels of Erk1/2, p38 MAPK and AMPK. Via application of each specific inhibitor of these kinases, FGF21 was found to prevent palmitate-induced PTEN activation and Akt inactivation via up-regulating Erk1/2-dependent p38 MAPK/AMPK signaling pathways. To confirm these in animal models, STZ-induced diabetic mice was treated with FGF21 once hyperglycemia was onset, which significantly prevented diabetes-induced cardiac apoptosis along with a prevention of diabetes-inhibited Erk1/2, p38 MAPK and AMPK phosphorylation. The in vivo cardiac protection of FGF21 from diabetes-induced cell death was also completely attenuated by the treatment with Erk1/2 inhibitor. In addition, in vivo administration of FGF21 to acute fatty acid-treated mice also protected fatty acid-induced cardiac cell death. More importantly, compared to wild-type mice, FGF21 gene knock-out (FGF21-KO) mice are highly susceptible to diabetes-induced cardiac cell death and inhibition of Erk1/2, p38 MAPK and AMPK phosphorylation, which could be prevented by administration of exogenous FGF21. These results strongly suggest that the early stage increase in FGF21 mRNA expression may represent an early protective mechanism; administration of exogenous FGF21 to diabetic mice or acute fatty acid-treated mice can prevent cardiac damage and cell death. The cardioprotection by FGF21 from diabetes is mediated by ERK1/2-dependent p38 MAPK and AMPK signaling pathway.
- © 2012 by American Heart Association, Inc.