Publications (5)23.19 Total impact
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Article: Histone Deacetylase Inhibition Attenuates Transcriptional Activity of Mineralocorticoid Receptor Through its Acetylation and Prevents Development of Hypertension.
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ABSTRACT: 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.Circulation Research 02/2013; · 9.49 Impact Factor -
Article: Upregulation of the Na(+)-K(+)-2Cl(-) cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats.
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ABSTRACT: The Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is upregulated in diverse models of hypertension. We hypothesized that NKCC1 is upregulated via histone modification in the aortas of angiotensin II (Ang II)-induced hypertensive rats. An osmotic mini-pump containing Ang II was implanted in the subcutaneous tissues of the backs of Sprague-Dawley (SD) rats for 7 days. The systolic blood pressure was recorded every day by the tail-cuff method. On days 3 and 7, the mesenteric arteries were excised, cut into rings, mounted in organ baths and subjected to vascular contraction. The levels of Nkcc1 mRNA and protein in the aortas were measured using real-time PCR and Western blotting, respectively. The histone modifications and recruited proteins at the Nkcc1 promoter were determined by chromatin immunoprecipitation. The inhibition of concentration-response curves to phenylephrine by bumetanide, an inhibitor of NKCCs, was greater in Ang II-infused rats than in sham-operated (sham) rats . The levels of Nkcc1 mRNA and protein in the aortas increased gradually as Ang II was infused into the rats. Acetylated histone H3 (H3Ac), an activating histone code, was increased but trimethylated histone H3 at lysine 27 (H3K27me3), a repressive histone code, was greatly decreased in Ang II-infused rats compared with sham. RNA polymerase II was recruited to the Nkcc1 promoter with increased KDM6b. We conclude that the NKCC1 is upregulated via histone modification in the aortas of Ang II-induced hypertensive rats. Thus, we suggest that this ion transporter is epigenetically upregulated by histone modification or DNA demethylation upon the development of hypertension.Hypertension Research 04/2012; 35(8):819-24. · 2.58 Impact Factor -
Article: Tissue-specific upregulation of angiotensin-converting enzyme 1 in spontaneously hypertensive rats through histone code modifications.
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ABSTRACT: The renin-angiotensin system has been implicated in the development of hypertension and damages several organs. The expressions of the components of a local renin-angiotensin system (RAS) in the hypertensive rats differ from those of the normotensive rats. We hypothesized that local tissue-specific upregulation of angiotensin-converting enzyme 1 (ACE1) in hypertension is caused by epigenetic changes. Adrenal gland, aorta, heart, kidney, liver, and lung tissues were excised from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Ace1 mRNA and protein expressions were measured by real-time PCR and Western blot, respectively. Promoter methylation was revealed by bisulfite sequencing. Histone modifications, such as histone 3 acetylation (H3Ac), fourth lysine trimethylation (H3K4me3), and ninth lysine dimethylation (H3K9me2), were quantified by chromatin immunoprecipitation (ChIP), followed by real-time PCR. The expressions and associations of chromatin remodeling genes were analyzed by real-time PCR and ChIP, respectively. Local tissues from SHRs showed higher expressions of Ace1 mRNA and protein than those from the WKY rats. Ace1 promoter was mostly unmethylated in all of the tissues from both strains. The Ace1 promoter regions of SHR tissues were more enriched with H3Ac and H3K4me3, except in the lungs. The adrenal glands, hearts, and kidneys of SHRs showed less enrichment with H3K9me2. Valsartan treatment in SHRs decreased local Ace1 mRNA and protein expressions, which were accompanied by higher H3K9me2, as well as less H3Ac and H3K4me3. In conclusion, ACE1 is upregulated in local tissues of SHRs via histone code modifications.Hypertension 03/2012; 59(3):621-6. · 6.21 Impact Factor -
Article: Enrichment of (pro)renin receptor promoter with activating histone codes in the kidneys of spontaneously hypertensive rats.
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ABSTRACT: The (pro)renin receptor [(P)RR] non-proteolytically, through conformational change, activates prorenin which can convert angiotensinogen to angiotensin I in addition to the classic conversion of angiotensinogen to angiotensin I by circulating renin. Since renal (P)RR is upregulated in hypertension and implicated in the pathogenesis of malignant hypertension, we hypothesized that (pro)renin receptor promoter is enriched with activating histone codes in the kidney of spontaneously hypertensive rats (SHR). The mRNA and protein expression levels were measured by real-time polymerase chain reaction (PCR) and western blot, respectively. The DNA methylation status of (P)RR promoter region was analyzed by bisulfite sequencing. The histone modifications were determined by chromatin immunoprecipitation followed by real-time PCR. The (P)RR mRNA expression in the kidney was about six times greater in SHR than in Wistar-Kyoto (WKY) rats. The (P)RR promoter was little methylated in the kidneys of both WKY and SHR. Acetylated histone H3 (H3Ac) and di-methylated histone H3 at lysine 4 (H3K4me2), activating histone codes, were about 25 and three times higher in SHR than in WKY, respectively. On the other hand, di-methylated histone H3 at lysine 9 (H3K9me2), a suppressive histone code, was 50 times lower in SHR than in WKY. These results suggest that the (P)RR promoter is enriched with activating histone codes in the kidneys of SHR.Journal of Renin-Angiotensin-Aldosterone System 07/2011; 13(1):11-8. · 2.44 Impact Factor -
Article: Promoter hypomethylation upregulates Na+-K+-2Cl- cotransporter 1 in spontaneously hypertensive rats.
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ABSTRACT: The Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is one of several transporters that have been implicated for development of hypertension since NKCC1 activity is elevated in hypertensive aorta and vascular contractions are inhibited by bumetanide, an inhibitor of NKCC1. We hypothesized that promoter hypomethylation upregulates the NKCC1 in spontaneously hypertensive rats (SHR). Thoracic aortae and mesenteric arteries were excised, cut into rings, mounted in organ baths and subjected to vascular contraction. The expression levels of nkcc1 mRNA and protein in aortae and heart tissues were measured by real-time PCR and Western blot, respectively. The methylation status of nkcc1 promoter region was analyzed by combined bisulfite restriction assay (COBRA) and bisulfite sequencing. Phenylephrine-induced vascular contraction in a dose-dependent manner, which was inhibited by bumetanide. The inhibition of dose-response curves by bumetanide was much greater in SHR than in Wistar Kyoto (WKY) normotensive rats. The expression levels of nkcc1 mRNA and of NKCC1 protein in aortae and heart tissues were higher in SHR than in WKY. Nkcc1 gene promoter was hypomethylated in aortae and heart than those of WKY. These results suggest that promoter hypomethylation upregulates the NKCC1 expression in aortae and heart of SHR.Biochemical and Biophysical Research Communications 05/2010; 396(2):252-7. · 2.48 Impact Factor
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2010–2012
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Kyungpook National University Hospital
Seoul, Seoul, South Korea
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