Epigenetic control of angiotensinogen and CYP11B2 gene expression in the hypertrophic hearts

Abstract

Purpose: The activation of local Renin-Angiotensin-Aldosterone System (RAAS) plays a pivotal role in the overall pathophysiology of the cardiovascular diseases. We have reported increased mRNA levels of angiotensinogen and CYP11B2 (aldosterone synthase gene) in the experimental hypertensive hearts. The mechanism of control of gene expression of each component of RAAS gene in the human hearts is unknown. We analyzed epigenetic alteration, which controls the gene of angiotensinogen and CYP11B2 in the human hypertrophic hearts. Methods: Nine cardiomyopathic hearts which were diagnosed by echo cardiography and MRI and six controls (non-cardiomyopathy) were analyzed. The mRNA expression levels of angiotensinogen and CYP11B2 were measured by real time PCR. The methylation status of the prompter region of angiotensinogen and CYP11B2 gene were measured using Bisulfite sequencing as reported elsewhere. Results: CpG dinucleotides in the CYP11B2 promoter were found to be hypermethylated in tissues with low expression, but not in those with high expression, of CYP11B2. CYP11B2 mRNA levels were inversely correlated with CYP11B2 methylation in human myocardium, and increased CYP11B2 mRNA levels were associated with CYP11B2 demethylation in the hypertrophic heart. CpG dinucleotides in the angiotensinogen gene promoter were also found to be hypermethylated in tissues with low expression. However, no correlation between angiotenisnogen mRNA levels and methylation was found in the hypertrophic hearts. Conclusions: Advances in understanding of epigenetic modifications of tissue RAAS in the progression of cardiac hypertrophy and heart failure could be of great significance in predicting the pace of disease progression, developing targeted therapeutic strategies in preventing the progression of cardiovascular diseases.