HISTONE DEACETYLASE INHIBITION ABOLISHES DEVELOPMENT OF HYPERTENSION
THROUGH INHIBITION OF MINERALOCORTICOID RECEPTOR TRANSACTIVATION IN
DOCA-INDUCED HYPERTENSIVE RATS
Inkyeom Kim, Hae-Ahm Lee
Department of Pharmacology, Cardiovascular Research Institute, Kyungpook National University
School of Medicine, Daegu, 700-422, Republic of Korea
Objective: Histone deacetylase inhibition by valproic acid prevents development of hypertension in SHR. We hypothesized that histone deacetylase inhibition (HDACi) abolishes development of hypertension through inhibition of Mineralocorticoid receptor Transactivation in deoxycorticosterone acetate (DOCA)-induced hypertension.
Design and Methods: Sprague-Dawley rats underwent uninephrectomy and received subcutaneous DOCA-salt (40 mg/Kg/Week) as well as 1% NaCl with or without 0.71% valproic acid (VPA) for 4 weeks. Blood pressures were measured by tail cuff method. The expressions of MR target genes and co-repressors were measured by real-time PCR. Recruitment of MR and RNA polymerase II into promoters of target genes was analyzed by chromatin immunoprecipitation (ChIP) assay. Wild type and mutant MR activities were measured by luciferase assay. HDAC isoform interacting with MR was determined by immunoprecipitation after expressing Flag-tagged HDACs and HA-tagged MR fusion proteins in HEK293 cells.
Results: VPA administration abolished DOCA-induced hypertension without changing body weight. DOCA infusion significantly increased the expressions of MR target genes, which were attenuated by VPA administration. VPA administration increased MR acetylation, resulting in decrease of MR binding on the promoter of target genes and of MR transactivation. HDAC3 was found to interact with MR.
Conclusions: HDAC inhibition abolishes development of hypertension through inhibition of mineralocorticoid receptor transactivation in deoxycorticosterone acetate (DOCA)-induced hypertension.