The recent emergence of epitranscriptomics provides an avenue for identifying RNA modifications implicated in the pathophysiology of human disease. To date, over 140 RNA modifications have been identified. These modifications are important because they can affect the fate of RNAs, including their decay, maturation, splicing, stability, and translational efficiency. Although RNA modifications have been reported in many tissues and disease contexts, detailed functional studies in the heart and cardiovascular disease (CVD) are still lacking.

A-to-I RNA editing occurs via RNA editing enzymes called "adenosine deaminases acting on RNA" (ADARs). These enzymes convert adenosine in double-stranded RNA to inosine. We have discovered that cathepsin S (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited. Such RNA editing enables the recruitment of stabilizing RNA-binding protein HuR to the 3’-UTR of CTSS transcripts, thereby controlling CTSS mRNA stability and expression. Interestingly, ADAR1 levels and the extent of CTSS RNA editing are associated with changes in CTSS levels in patients with atherosclerotic vascular disease (Nature Medicine, 2016).

Genetic ablation of Adar1 or Adar2 results in embryonic or postnatal lethality, respectively, in mice. Adar1 null mice exhibit normal development up to E10.5, but display enhanced cellular apoptosis in multiple tissues, including the heart, and late-stage embryonic death. It remains unclear, however, whether the failure to thrive is due to reduced generation during development and/or cardiomyocyte survival. By genetically ablating Adar1 in developing cardiomyocytes, we demonstrated for the first time that Adar1 has important functions in developing hearts by controlling cardiomyocyte survival and proliferation (Circulation Research, 2020).