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Epigenetic regulation of physiological cardiac hypertrophy by O‐GlcNAc and histone deacetylases in diabetes
Author(s) -
Cox Emily J,
Marsh Susan A
Publication year - 2013
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.27.1_supplement.738.2
Subject(s) - hdac1 , endocrinology , medicine , histone deacetylase 2 , diabetes mellitus , muscle hypertrophy , histone , chemistry , epigenetics , histone deacetylase , gene , biochemistry
Exercise causes physiological cardiac hypertrophy, and type 2 diabetes blunts hypertrophic signaling. Diabetic hearts have elevated levels of O‐linked β‐N‐acetylglucosamine (O‐GlcNAc), which post‐translationally modifies a complex of mSin3A and histone deacetylases (HDACs) 1 and 2. mSin3A/HDAC1/2 regulates hypertrophy and is targeted to genes by REST and O‐GlcNAc transferase (OGT). We examined the role of O‐GlcNAc in these mechanisms in 8‐week‐old diabetic ( db/db ) and non‐diabetic C57BL/6J mice randomized to exercise or sedentary groups for 4 weeks. Db/db mice had higher heart weight to tibia length (5.4±0.1 vs 4.7±0.1 mg/mm), fasting glucose (10.1±3.2 vs 5.5±1.5 mmol/L), and body weight (39.1±2.5 vs 20.1±1.2 g). Db/db hearts had higher levels of O‐GlcNAc and OGT, but lower mSin3A, HDAC1, and HDAC2. Conversely, HDAC2 expression and HDAC1/2 activity were higher in db/db hearts, and α‐actin and BNP expression were lower. In db/db hearts, immunoprecipitation showed that mSin3A was more O‐GlcNAcylated and more associated with REST, and OGT was less associated with HDAC2. Exercise corrected these changes, showing that diabetes and exercise have interacting effects on the epigenetic control of hypertrophy.