Modulation of ADARs mRNA expression in congenital heart defect patients

Abstract

27Adenosine (A) to inosine (I) RNA editing, is a hydrolytic deamination reaction catalyzed by 28 adenosine deaminase (ADAR) acting on RNA enzymes. RNA editing is a molecular process that 29 involves the post-transcriptional modification of RNA transcripts. Interestingly, few studies have 30 been carried out to determine the role of RNA editing in vascular disease. The current study 31 found that in blood samples positive for congenital heart disease (CHD) ADAR1 and ADAR2 32 expression change at RNA level was opposite to each other. That is, an increase of ADAR1 33 mRNA was noticed in human CHD cases, whereas ADAR2 mRNA was vastly down-regulated. 34The increase in ADAR1 may be explained by the stress induced by CHD. The dramatic decrease 35 in ADAR2 in CHD cases was unexpected and prompted further investigation into its effects on 36 the heart. Therefore we performed expression analysis on a microarray data encompassing 37 ischemic and non-Ischemic cardiomyopathy patient myocardial tissues. A strong down-38 regulation of ADAR2 was observed in both ischemic and especially non-ischemic cases. 39However, ADAR1 showed a mild increase in the case of non-ischemic myocardial tissues. To 40 further explore the role of ADAR2 with respect to heart physiology. We selected a protein 41 coding gene filamin B (FLNB). FLNB is known to play an important role in heart development. 42Although there were no observable changes in its expression, the editing levels of FLNB 43 dropped dramatically in ADAR2 -/mice. We also performed miRNA profiling from ADAR2 -/-44 mice heart tissue revealed a decrease in expression of miRNAs. It is established that aberrant 45 expression of these miRNAs is often associated with cardiac defects. This study proposes that 46 sufficient amounts of ADAR2 might play a vital role in preventing cardiovascular defects. 47 48 KEYWORDS 49