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

Abstract

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.

Endothelial Cell Serum and Glucocorticoid Regulated Kinase 1 (SGK1) Mediates Vascular Stiffening

“…Isolated heart, left and right kidney, as well as liver weights were significantly increased while epididymal fat were significantly decreased in DOCA-salt-treated animals (Supplemental Figure S5D-E), suggesting that 42 day-treatments of DOCA-salt might affect overall body fat distribution and induces hypertrophy in heart, kidney and liver. It is well documented that DOCA-Salt administration induces both cardiac 26,35,36 and renal hypertrophy and fibrosis 26,37 . Indeed, a previous study 38 has shown that 12 weeks of DOCA-salt administration induced marked glomerular sclerosis and tubulointerstitial damage with interstitial fibrosis and inflammation in kidneys, which were prevented in mice with global SGK1 deletion.…”

EGCG prevents pressure overload‑induced myocardial remodeling by downregulating overexpression of HDAC5 in mice

“…HDACs are considered effective interventional targets for the treatment of numerous types of human disease ( 44 , 45 ). Studies have confirmed that HDACs are involved in the occurrence and development of cardiac hypertrophy in mice ( 46 ), and that HDAC-specific inhibitors may improve heart failure and maintain normal systolic function of the heart ( 47 ). It has also been reported that deer antler in traditional Chinese medicine improves cardiac hypertrophy and CHF by regulating histone acetylation modification ( 48 ).…”

HDAC11 regulates expression of C/EBPβ and immunosuppressive molecules in myeloid-derived suppressor cells

“…Mice lacking C/EBPβ in the BM compartment lose the ability to differentiate from IMCs into pathologically active MDSCs through a reduction of Arg1 and NOS2 proteins 13 . A recent study demonstrated that the expression of C/EBPβ is up‐regulated by HDAC inhibitors 24 . However, the genetic or epigenetic mechanism(s) regulating C/EBPβ gene expression in MDSCs have remained poorly understood.…”