RNA editing in cardiovascular health and disease

Figures

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  Fig. 1. Diagram of adenosine (A)-to-inosine (I) RNA editing. A ADAR (adenosine deaminase acting on RNA) enzymes recognize specific sites on double-stranded RNA (dsRNA) and deaminate its adenosine, thereby converting it to inosine. B Editing of Alu double-stranded RNAs (dsRNAs) and its consequences. RNA editing mostly occurs on regions of inverted Alu repeats in the introns and untranslated regions of the genome. These Alu repeats form intramolecular RNA duplexes (Alu dsRNAs) which serve as substrates for ADAR enzymes for A-to-I RNA editing. Reported consequences of A-to-I RNA editing include preventing MD5 sensing of endogenous dsRNA as non-self, and altering the sequence, stability, localization, and function of RNA molecules. C The various domains of the two ADAR1 isoforms (ADAR1p150 and ADAR1p110) and ADAR2. All these enzymes share a conserved catalytic deaminase domain (indicated in blue) and two or three double-stranded RNA-binding domains (dsRBD, indicated in green) that determine substrate specificity. The two isoforms of ADAR1 differ in the number of Z-nucleic acid-binding domains (Zα and Zβ; indicated in yellow), which are the main distinguishing features between them. NES,…

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  Fig. 2. Adenosine (A)-to-inosine (I) editing of transcripts of individual genes implicated in cardiovascular disease. A ADAR1-mediated editing of Alu repeats in the 3’-untranslated region of the cathepsin S (CTSS) gene transcript facilitates its interaction with the RNA binding protein HuR, consequently increasing CTSS transcript stability and CTSS expression. Cathepsin S promotes atherosclerotic cardiovascular disease (ASCVD) and aortic aneurysm by degrading vascular extracellular matrix. B A-to-I editing of exon 42 of the filamin A (FLNA) gene transcript leads to a substitution of the glutamine (Q) at residue 2341 of the filamin A protein by an arginine (R), which reduces vascular smooth muscle cell (VSMC) contractility and therefore diastolic blood pressure. C A-to-I editing of the insulin-like growth factor binding protein-7 (IGFBP7) gene transcript results in a substitution of the glutamic acid (E) at residue 69 of the IGFBP7 protein by a glycine (G). The rate of A-to-I editing in IGFBP7 transcripts within cardiovascular tissues is significantly elevated in patients with ischemic cardiomyopathy. D ADAR1-mediated editing of transcripts of the smooth muscle myosin heavy chain (MYH11)…

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  Fig. 3. Induction of A-to-I RNA editing by LEAPER 2.0. Circ-arRNA (circular ADAR recruiting RNA) anneals with the target transcript to form dsRNA substrate, which in turn recruits endogenous ADARs for targeted editing. The abundance of arRNA in cells is positively correlated with editing efficiency. Circ-arRNA, due to its higher stability, can enhance editing efficiency. The removal of uridines opposite non-target adenosines on circ-arRNA effectively prevents off-target adenosine editing. U, uridine; dd, deaminase domain; dsRBD, dsRNA-binding domain.