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FGF13 Is a Novel Regulator of NF-?B and Potentiates Pathological Cardiac Hypertrophy.

ABSTRACT: FGF13 is an intracellular FGF factor. Its role in cardiomyopathies has been rarely investigated. We revealed that endogenous FGF13 is up-regulated in cardiac hypertrophy accompanied by increased nuclear localization. The upregulation of FGF13 plays a deteriorating role both in hypertrophic cardiomyocytes and mouse hearts. Mechanistically, FGF13 directly interacts with p65 by its nuclear localization sequence and co-localizes with p65 in the nucleus in cardiac hypertrophy. FGF13 deficiency inhibits NF-?B activation in ISO-treated NRCMs and TAC-surgery mouse hearts, whereas FGF13 overexpression shows the opposite trend. Moreover, FGF13 overexpression alone is sufficient to activate NF-?B in cardiomyocytes. The interaction between FGF13 and p65 or the effects of FGF13 on NF-?B have nothing to do with I?B. Together, an I?B-independent mechanism for NF-?B regulation has been revealed in cardiomyocytes both under basal and stressful conditions, suggesting the promising application of FGF13 as a therapeutic target for pathological cardiac hypertrophy and heart failure.

SUBMITTER: Sun J

PROVIDER: S-EPMC7567043 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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FGF13 Is a Novel Regulator of NF-κB and Potentiates Pathological Cardiac Hypertrophy.

Sun Jia J Niu Chao C Ye Weijian W An Ning N Chen Gen G Huang Xiaozhong X Wang Jianan J Chen Xixi X Shen Yingjie Y Huang Shuai S Wang Ying Y Wang Xu X Wang Yang Y Jin Litai L Cong Weitao W Li Xiaokun X

iScience 20200930 10

FGF13 is an intracellular FGF factor. Its role in cardiomyopathies has been rarely investigated. We revealed that endogenous FGF13 is up-regulated in cardiac hypertrophy accompanied by increased nuclear localization. The upregulation of FGF13 plays a deteriorating role both in hypertrophic cardiomyocytes and mouse hearts. Mechanistically, FGF13 directly interacts with p65 by its nuclear localization sequence and co-localizes with p65 in the nucleus in cardiac hypertrophy. FGF13 deficiency inhibi ...[more]

PMID: 33089113

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Project description:BackgroundPathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed.MethodsThe expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d.FindingsmiR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes.InterpretationOverexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy.FundingThis work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).

Dataset Information

FGF13 Is a Novel Regulator of NF-?B and Potentiates Pathological Cardiac Hypertrophy.

Publications

FGF13 Is a Novel Regulator of NF-κB and Potentiates Pathological Cardiac Hypertrophy.

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