MetaTOC stay on top of your field, easily

Upregulation of C/EBPβ and TSC2 by an HDAC inhibitor CG200745 protects heart from DOCA‐induced hypertrophy

, , , , , , , , ,

Clinical and Experimental Pharmacology and Physiology

Published online on


--- - |2 Summary Histone deacetylases (HDACs) 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 (HDAC11). HDAC inhibition attenuates cardiac hypertrophy through suppression of the mechanistic target of rapamycin complex1 (mTORC1) signaling. HDAC inhibitors upregulate the expression of tuberous sclerosis complex 2 (TSC2), an mTORC1 inhibitor. However, the molecular mechanism underlying HDAC inhibitor‐mediated upregulation of TSC2 is unclear. We hypothesized that an HDAC inhibitor, CG200745 (CG), ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling by upregulating of the CCAAT/enhancer‐binding protein‐β (C/EBP‐β)/TSC2 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 TSC2 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 TSC2 promoter region was analyzed by chromatin immunoprecipitation (ChIP). CG treatment increased the expression of TSC2. 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 mTORC1 signaling via upregulation of the C/EBP‐β/TSC2 pathway in DOCA‐induced hypertensive rats. - 'Clinical and Experimental Pharmacology and Physiology, EarlyView. '