Histone Deacetylase Inhibition Attenuates Transcriptional Activity of Mineralocorticoid Receptor Through its Acetylation and Prevents Development of Hypertension
Rationale: Inhibition of histone deacetylases (HDAC) results in attenuated development of hypertension in DOCA-induced hypertensive rats and spontaneously hypertensive rats. However, the molecular mechanism remains elusive.
Objective: We hypothesized that HDAC inhibition (HDACi) attenuates transcriptional activity of mineralocorticoid receptor (MR) through its acetylation and prevents development of hypertension in DOCA-induced hypertensive rats.
Methods and Results: Expression of MR target genes was measured by quantitative real-time PCR (qRT-PCR). Recruitment of MR and RNA polymerase II on promoters of target genes was analyzed by chromatin immunoprecipitation (ChIP) assay. Live cell imaging was performed for visualization of nuclear translocation of MR. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation (IP) with anti-MR antibody. Transcriptional activity of MR was determined by luciferase assay. For establishment of a hyperaldosteronism animal, Sprague-Dawley rats underwent uninephrectomy and received subcutaneous injection of 40 mg/Kg/week of deoxycorticosteron acetate (DOCA) as well as drinking water containing 1% NaCl. Treatment with a HDAC class I inhibitor resulted in reduced expression of MR target genes in accordance with reduced recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes. HDACi promoted MR acetylation, leading to decreased transcriptional activity of MR. Knockdown or inhibition of HDAC3 resulted in reduced expression of MR target genes induced by mineralocorticoids.
Conclusions: These results indicate that HDACi attenuates transcriptional activity of MR through its acetylation and prevents development of hypertension in DOCA-induced hypertensive rats.
- valproic acid
- mineralocorticoid receptor
- animal model cardiovascular disease
- gene transcription
- gene regulation
- Received January 27, 2013.
- Revision received February 16, 2013.
- Accepted February 19, 2013.
- Copyright © 2013, Circulation Research