{
  "abstract": "Introduction In patients with or at high risk for atherosclerotic cardiovascular disease, residual inflammatory risk is a strong predictor of future cardiovascular events. Post-transcriptional regulation of gene expression by RNA-based mechanisms, like adenosine-to-inosine RNA editing, can overwrite transcriptional programs and determine cell signaling in disease. Whether the enzyme ADAR2 that catalyzes the deamination of adenosine to inosine in RNA molecules, is involved in atherosclerosis remains elusive.Methods Expression levels of ADAR2 were measured in peripheral blood mononuclear cells derived from 687 individuals at risk for atherosclerotic vascular disease. Structural vascular measurements were used, and study participants were followed for major adverse cardiovascular events. Experimental atherosclerosis was assessed in ADAR2/ApoE double knockout mice fed with a Western diet. Mechanistic experiments involved human aortic endothelial cells with ADAR2 knockdown followed by inflammatory stimulation.Results Increased ADAR2 mRNA expression was independently associated with increased hs-CRP, a marker of metabolic inflammation, and with the presence of coronary artery disease. Increased ADAR2 expression was associated with accelerated burden of atheromatosis in the carotid/femoral arteries or the carotid arteries after a median follow-up of 33 months. Patients at the highest ADAR2 tertile had a higher incidence of major adverse cardiovascular events, defined as all-cause death and/or myocardial infarction compared to their counterparts in the lower tertiles after adjustment for the core model. ADAR2 knockout mice exhibited attenuated atherosclerotic lesion formation, while cholesterol and triglyceride profiles of these animals were similar. Absence of ADAR2 in atherosclerotic mice reduced the levels of several circulating pro-inflammatory mediators. Mechanistically, ADAR2 silencing attenuated inflammatory activation in endothelial cells and suppressed a broad cytokine-driven transcriptional programs.Conclusion ADAR2 is clinically associated with an adverse cardiometabolic and inflammatory profile in patients with atherosclerotic cardiovascular disease, and it functionally amplifies cytokine-responsive endothelial signalling. ADAR2-dependent RNA regulation represents a candidate biomarker and therapeutic axis for vascular inflammation.",
  "authors": [
    {
      "affiliations": [
        "Newcastle University, Newcastle upon Tyne, United Kingdom"
      ],
      "name": "Simon Tual-Chalot"
    },
    {
      "affiliations": [
        "Heidelberg University, Mannheim, Germany"
      ],
      "name": "Michael Amponsah-Offeh"
    },
    {
      "affiliations": [
        "University of Athens, Athens, Greece"
      ],
      "name": "Georgios Georgiopoulos"
    },
    {
      "affiliations": [
        "Heidelberg University, Mannheim, Germany"
      ],
      "name": "Marco Sachse"
    },
    {
      "affiliations": [
        "Heidelberg University, Mannheim, Germany"
      ],
      "name": "Maria Polycarpou-Schwarz"
    },
    {
      "affiliations": [
        "University of Athens, Athens, Greece"
      ],
      "name": "Kimon Stamatelopoulos"
    },
    {
      "affiliations": [
        "Heidelberg University, Mannheim, Germany"
      ],
      "name": "Konstantinos Stellos"
    }
  ],
  "title": "340 RNA editing controls atherosclerotic cardiovascular disease by promoting inflammation",
  "uid": "8a524d91-cfae-5a77-a4b3-9009aa4ba86f"
}