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Inhibition of HDAC, especially HDAC3, prevents diabetic cardiomyopathy in OVE26 mice via epigenetic inhibition of ERK1/2‐DUSP5 pathway
Author(s) -
Xu Zheng,
Cai Lu
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.977.4
Subject(s) - diabetic cardiomyopathy , hdac3 , histone deacetylase , medicine , pathogenesis , inflammation , fibrosis , hdac1 , histone deacetylase inhibitor , pharmacology , endocrinology , histone , cardiomyopathy , chemistry , heart failure , biochemistry , gene
Inhibition of histone deacetylase (HDAC) phenomenally protects against streptozotocin‐induced cardiomyopathy. To explore the mechanisms, male type 1 diabetes OVE26 mice and age‐matched wild type mice were given HDAC inhibitor (valproic acid, VPA), selective HDAC3 inhibitor (RGFP966) or vehicle for 3 months. These mice then were sacrificed immediately or 3 months after the end of 3‐month treatment (6 months). Cardiac function and pathological changes (hypertrophy, fibrosis, inflammation and oxidative damage) were assessed by echocardiography and histopathological examination. Both VPA and RGFP966 significantly prevented DCM, reflected by the prevention of diabetes‐induced cardiac dysfunction, hypertrophy and fibrosis, along with cardiac oxidative stress and inflammation. The protection from DCM was persistently observed even at the 3 rd month after the end of 3‐month HDAC inhibition, suggesting the “preventive memory” of DCM by HDAC inhibition. Mechanistically phosphorylated ERK1/2 that is a well‐known initiator to cardiac hypertrophy was significantly increased, which was prevented by VPA and RGFP966. Meanwhile the DUSP5 (Dual Specificity Phosphatase 5), an ERK1/2 negatively regulating nuclear phosphatase, was oppositely changed. Chromatin immunoprecipitation assays showed the elevated histone H3 acetylation at DUSP5 gene promoter in both 3 months and 6 months. These findings suggest that diabetes increases HDAC3 activity to deacetylate DUSP5 for derepressing ERK1/2 inhibition, leading to its initiation of DCM pathogenesis, which is preventable by HDAC inhibition. The epigenetic mechanism responsible for the pathogenesis of DCM and its preventable by HDAC inhibition explains its preventive memory. Therefore, these results suggested the therapeutic potential of HDAC inhibition in treating DCM.