Modulation of ADARs mRNA expression in congenital heart defect patients

Abstract

Adenosine (A) to inosine (I) RNA editing, is a hydrolytic deamination reaction catalyzed by adenosine deaminase (ADAR) acting on RNA enzymes. RNA editing is a molecular process that involves the post-transcriptional modification of RNA transcripts. Interestingly, few studies have been carried out to determine the role of RNA editing in vascular disease. The current study found that in blood samples positive for congenital heart disease (CHD) ADAR1 and ADAR2 expression change at RNA level was opposite to each other. That is, an increase of ADAR1 mRNA was noticed in human CHD cases, whereas ADAR2 mRNA was vastly down-regulated. The increase in ADAR1 may be explained by the stress induced by CHD. The dramatic decrease in ADAR2 in CHD cases was unexpected and prompted further investigation into its effects on the heart. Therefore we performed expression analysis on a microarray data encompassing ischemic and non-Ischemic cardiomyopathy patient myocardial tissues. A strong down-regulation of ADAR2 was observed in both ischemic and especially non-ischemic cases. However, ADAR1 showed a mild increase in the case of non-ischemic myocardial tissues. To further explore the role of ADAR2 with respect to heart physiology. We selected a protein coding gene filamin B (FLNB). FLNB is known to play an important role in heart development. Although there were no observable changes in its expression, the editing levels of FLNB dropped dramatically in ADAR2-/- mice. We also performed miRNA profiling from ADAR2 -/- mice heart tissue revealed a decrease in expression of miRNAs. It is established that aberrant expression of these miRNAs is often associated with cardiac defects. This study proposes that sufficient amounts of ADAR2 might play a vital role in preventing cardiovascular defects.