SY 15-4 ROLE OF HISTONE DEACETYLASES IN REGULATING ENDOTHELIAL AND VASCULAR FUNCTION

Abstract

Histone deacetylases (HDACs) act as co-repressors in gene transcription by erasing the acetylation of histones, resulting in epigenetic gene silencing. Recent studies revealed that HDAC inhibitors attenuated blood pressure of several hypertensive animal models such as spontaneously hypertensive rats, hyperaldosteronism rats, angiotensin II-induced hypertensive rats and pulmonary hypertensive rats. Unexpectedly, microarray studies uncovered that administration of HDAC inhibitors decreased expression of some genes for example extracellular matrix proteins, oxidative stress-related proteins, cytokines, chemokines and ion transporters, mostly targets of corticoid receptors. Corticoid-induced hypertensive animal model was established by infusion of adrenocorticotropic hormone (40 ng/kg/day), deoxycorticosterone acetate (40 mg/kg), and dexamethasone (100 μg/kg/day) with osmotic mini-pump. Valproic acid (VPA), a class I and IIa HDAC inhibitor administration significantly decreased corticoid-induced hypertension. VPA administration increased acetylation level of Mineralocorticoid receptor (MR), which was closely related with decreased binding affinity with hormone response element in the promoters of target genes such as glucocorticoid induced leucine zipper (Gilz) and serum glucocorticoid regulated kinase-1 (Sgk-1). HDAC3 and HDAC4 were interacted with MR after stimulation of aldosterone (10 nmol/L) for 30 min. HDAC4 inhibitor showed no effect on acetylation level and promoter binding affinity of MR. HDAC4 played a role as a scaffold between MR and HDAC3. In conclusion, HDAC inhibitors increased acetylation of corticoid receptor, resulted in decreased transcriptional activity of it and blocked corticoid induced-hypertension.