DNA Methylation of the Angiotensinogen Gene, AGT , and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

• Published in: International journal of molecular sciences Vol. 22; no. 9; p. 4587
• Main Authors: Takeda, Yoshimichi, Demura, Masashi, Yoneda, Takashi, Takeda, Yoshiyu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.04.2021; MDPI
• Subjects: Adipose tissue; Adrenal glands; Aldosterone; Aldosterone synthase; Angiotensin; Angiotensin II; Angiotensinogen; Binding sites; Blood pressure; Cardiomyopathy; cardiovascular disease; Cardiovascular diseases; CpG islands; Demethylation; Deoxyribonucleic acid; Diabetes; DNA; DNA methylation; Enzymes; Epigenetics; Gene expression; Heart; Hypertension; Mammals; MeCP2 protein; Metabolic disorders; Methyl-CpG binding protein; methylation; Nuclear receptors; Nurr1 protein; Pathogenesis; Phenotypes; Proteins; Review; Salt; Transcription factors; Transgenic animals; Tumors; cardiovascular disease; salt; angiotensinogen; aldosterone; methylation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22094587

Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene is regulated by angiotensin II and potassium. DNA methylation negatively regulates and expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the promoter region, thereby converting the phenotype of expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac expression. CpG dinucleotides in the promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated promoter. Low salt intake and angiotensin II infusion lead to upregulation of expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both and contribute to the pathogenesis of cardiovascular diseases.