Lysine deacetylase inhibition attenuates hypertension and is accompanied by acetylation of mineralocorticoid receptor instead of histone acetylation in spontaneously hypertensive rats.
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.
Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.|National Development Institute of Korean Medicine, Gyeongsan-si, Gyeongsangbuk-do, 38540, South Korea.
Young Mi
YM
Seok
Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.|Department of Pharmacology, School of Medicine, Kyungpook National University, 680 GugchaeBosang Street, Daegu, 41944, Republic of Korea.|Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.
Hae Ahm
HA
Lee
Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.|Department of Anatomy. School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.
Kwon Moo
KM
Park
Department of Food Nutrition and Cookery, Keimyung College University, Daegu, Republic of Korea.
Mi-Hyang
MH
Hwangbo
Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea. inkim@knu.ac.kr.|Department of Pharmacology, School of Medicine, Kyungpook National University, 680 GugchaeBosang Street, Daegu, 41944, Republic of Korea. inkim@knu.ac.kr.|Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea. inkim@knu.ac.kr.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea. inkim@knu.ac.kr.
In Kyeom
IK
Kim
D000107:Acetylation; D000367:Age Factors; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D000959:Antihypertensive Agents; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D012319:RNA Polymerase II; D018161:Receptors, Mineralocorticoid; D014157:Transcription Factors; D014635:Valproic Acid; D000099184:Serum-Glucocorticoid Regulated Kinases; C498609:Tsc22d3 protein, rat
Acetylation; Hypertension; Inhibition of lysine deacetylase; Mineralocorticoid receptor; Spontaneously hypertensive rats