摘要
As a classically known mitogen,fibroblast growth factor 1(FGF1)has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection.Here,we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy(DCM)patients,indicating that FGF1 is a potential therapeutic target for DCM.We found that treatment with a FGF1 variant(FGF1^(△HBS))with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function.RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1AHBS treatment.Both in vivo and in vitro studies indicate that FGF1^(△HBS) exerted these beneficial effects by markedly reducing mitochondrial fragmentation,reactive oxygen species(ROS)generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5;AMP-activated protein kinase(AMPK)/Nur77-dependent manner,all of which were not observed in the AMPK null mice.The favorable metabolic activity and reduced proliferative properties of FGF1^(△HBS) testify to its promising potential for use in the treatment of DCM and other metabolic disorders.
基金
This work was supported by Grants from National Key R&D Program of China(2017YFA0506000)(to X.L.and Z.H.)
Natural Science Foundation of China(81874323,92057122 and 81903532 to Z.H.and D.W.)
CAMS Innovation Fund for Medical Sciences(2019-12M-5-028 to X.L)
Zhejiang Provincial Natural Science Foundation(LY18H070002 to Y.W).