Lysine deacetylase inhibition attenuates hypertension and is accompanied by acetylation of mineralocorticoid receptor instead of histone acetylation in spontaneously hypertensive rats

Abstract

Inhibition of lysine deacetylase (KDAC) attenuated development of hypertension in spontaneously hypertensive rats (SHRs). We hypothesized that KDAC inhibition attenuates hypertension and is accompanied by acetylation of mineralocorticoid receptors (MR) instead of histone acetylation in SHRs. Valproate (VPA, 0.71 % wt/vol), an inhibitor of class I KDACs, was administered in drinking water to 7-week-old SHRs and Wistar Kyoto rats for 11 weeks. MR acetylation was determined by immunoprecipitation with anti-MR antibody followed by western blot with anti-acetyl-lysine antibody. Expression levels of acetylated histone H3, KDACs, MR target genes, or MR corepressors in the kidney cortex were measured by using western blot analysis or real-time PCR. Recruitment of MR and RNA polymerase II (Pol II) and histone modifications on promoters of target genes were analyzed by performing a chromatin immunoprecipitation (ChIP) assay. Treatment of SHR with VPA increased MR acetylation without affecting MR expression, which attenuated development of hypertension in SHR VPA decreased expression of KDAC class I but globally increased acetylated histone H3. Although VPA treatment increased histone 3 acetylation (H3Ac) and trimethylation of the fourth lysine (H3K4me3) in the promoter regions of MR target genes, it decreased the expression of target genes as well as recruitment of MR and Pol II. These results suggest that KDAC inhibition attenuates the development of hypertension in SHRs and is accompanied by acetylation of MR that is independent of histone acetylation.

Acetylation of nuclear receptors in health and disease: an update

“…HDAC3 interaction with MR reduces its transcriptional activity [100], and HDAC4 was identified as a necessary scaffold for assembly of the MR‐HDAC3 complex. Inhibition of class I HDACs promoted MR acetylation and abrogating hypertension in spontaneously hypertensive rats [107] HDAC2 [98] and SIRT1 [108] govern GR deacetylation, which is required for GR binding to NFκB with consequent repression of inflammation [109]. Increasing acetylation of residue K295 of HSP90 by inhibiting HDAC6 weakened HSP90 interaction with the MR [110] and GR [111] and supported nuclear import of both receptors.…”

Acetylated Histone Modifications: Intersection of Diabetes and Atherosclerosis

“…28–30 In addition, hypertension, which is closely related to diabetes, is also negatively regulated by HDACs. 31…”

“…[28][29][30] In addition, hypertension, which is closely related to diabetes, is also negatively regulated by HDACs. 31 In addition to conventional deacetylation, some HDACs have been shown to have nondeacetylase effects in long-term experiments, as exemplified by class II and HDACs. These HDACs can enter the cytoplasm during specific cardiovascular events and may only be associated with their own low deacetylation function.…”

Posttranslational Modifications of the Mineralocorticoid Receptor and Cardiovascular Aging

“…Increased acetylation led to decreased MR transcriptional activity with reduced expression of MR target genes and attenuated MR and Pol II recruitment to specific hormone response elements. No effect on MR expression or translocation was found (Lee et al, 2013;Kang et al, 2015;Lee et al, 2015;Seo et al, 2015;Seok et al, 2016). Besides having lysine acetyltransferase activity, CBP and p300 can also function as transcriptional adaptors and thereby MR coactivators to enhance MR activity (Fuse et al, 2000;Peter et al, 2017).…”

“…Furthermore, HDAC inhibition attenuated pathophysiological MR effects like hypertension, hypertrophy, inflammation and fibrosis in vivo in animal models of spontaneous hypertension and hyperaldosteronism (Cardinale et al, 2010;Iyer et al, 2010;Lee et al, 2013;Kang et al, 2015;Seok et al, 2016). Although treatment with VPA not only enhanced MR acetylation but also increased histone-3-acetylation (H3Ac) and trimethylation (H3K4me3) in the promoter regions of MR target genes, expression of MR target genes was decreased, and the development of hypertension in deoxycorticosterone acetateinduced hypertensive rats and spontaneously hypertensive rats (SHR) was prevented (Seok et al, 2016). These results suggest that HDAC inhibition attenuates the development of hypertension in SHR through acetylation of MR and independent of histone effects.…”