In:
Clinical and Experimental Pharmacology and Physiology, Wiley, Vol. 46, No. 3 ( 2019-03), p. 226-236
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0305-1870
,
1440-1681
DOI:
10.1111/cep.2019.46.issue-3
DOI:
10.1111/1440-1681.13022
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2020033-X
SSG:
15,3
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