Affiliation:
1. From the Department of Pharmacology (H.-A.L., H.-M.C., D.-Y.L., I.K.K.), Cardiovascular Research Institute (H.-A.L., K.-C.K., I.K.K.), Department of Physiology (H.S.H.), and Cell and Matrix Research Institute (H.-A.L., I.K.K.), Kyungpook National University School of Medicine, Daegu, Republic of Korea.
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Cited by
62 articles.
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