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Upregulation of C/ EBP β and TSC 2 by an HDAC inhibitor CG 200745 protects heart from DOCA ‐induced hypertrophy
Author(s) -
Lee Eunjo,
Lee HaeAhm,
Kim Mina,
Do Ga young,
Cho HyunMin,
Kim Gun Jik,
Jung Hanna,
Song Jung Hup,
Cho Joong Myung,
Kim Inkyeom
Publication year - 2019
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13022
Subject(s) - downregulation and upregulation , chemistry , microbiology and biotechnology , pharmacology , medicine , biochemistry , biology , gene
Summary Histone deacetylases ( HDAC s) are a vast family divided into four major classes: class I (1, 2, 3, and 8), class II (4, 5, 6, 7, 9 and 10), class III (sirtuin family) and class IV ( HDAC 11). HDAC inhibition attenuates cardiac hypertrophy through suppression of the mechanistic target of rapamycin complex1 ( mTORC 1) signaling. HDAC inhibitors upregulate the expression of tuberous sclerosis complex 2 ( TSC 2), an mTORC 1 inhibitor. However, the molecular mechanism underlying HDAC inhibitor‐mediated upregulation of TSC 2 is unclear. We hypothesized that an HDAC inhibitor, CG 200745 ( CG ), ameliorates cardiac hypertrophy through the inhibition of mTORC 1 signaling by upregulating of the CCAAT /enhancer‐binding protein‐β (C/ EBP ‐β)/ TSC 2 pathway. To establish a cardiac hypertrophy model, deoxycorticosterone acetate ( DOCA , 40 mg/kg/wk) was subcutaneously injected for 4 weeks into Sprague‐Dawley rats. All rats were unilaterally nephrectomized and had free access to drinking water containing 1% NaCl with or without CG of different concentrations. The expression level of TSC 2 and C/ EBP ‐β was measured by quantitative real‐time PCR ( qRT ‐ PCR ) and western blot analysis. Acetylation of C/ EBP ‐β was analyzed by immunoprecipitation. The recruitment of C/ EBP ‐β and polymerase II (Pol II ) on TSC 2 promoter region was analyzed by chromatin immunoprecipitation (Ch IP ). CG treatment increased the expression of TSC 2. In addition, CG treated rats showed an increased in the expression and acetylation of C/ EBP ‐β, owing to the increase in the recruitment of C/ EBP ‐β and Pol II at Tsc2 gene promoter. Thus, CG ameliorates cardiac hypertrophy through the inhibition of mTORC 1 signaling via upregulation of the C/ EBP ‐β/ TSC 2 pathway in DOCA ‐induced hypertensive rats.