Increased A-to-I RNA editing in atherosclerosis and cardiomyopathies

Abstract

Adenosine-to-inosine RNA editing is essential to prevent undesired immune activation. This diverse process alters the genetic content of the RNA and may recode proteins, change splice sites and miRNA targets, and mimic genomic mutations. Recent studies have associated or implicated aberrant editing with pathological conditions, including cancer, autoimmune diseases, and neurological and psychiatric conditions. RNA editing patterns in cardiovascular tissues have not been investigated systematically so far, and little is known about its potential role in cardiac diseases. Some hints suggest robust editing in this system, including the fact that ADARB1 (ADAR2), the main coding-sequence editor, is most highly expressed in these tissues. Here we characterized RNA editing in the heart and arteries and examined a contributory role to the development of atherosclerosis and two structural heart diseases -Ischemic and Dilated Cardiomyopathies. Analyzing hundreds of RNA-seq samples taken from the heart and arteries of cardiac patients and controls, we find that global editing, alongside inflammatory gene expression, is increased in patients with atherosclerosis, cardiomyopathies, and heart failure. We describe a single recoding editing site and suggest it as a target for focused research. This recoding editing site in the IGFBP7 gene is one of the only evolutionary conserved sites between mammals, and we found it exhibits consistently increased levels of editing in these patients. Our findings reveal that RNA editing is abundant in arteries and is elevated in several key cardiovascular conditions. They thus provide a roadmap for basic and translational research of RNA as a mediator of atherosclerosis and non-genetic cardiomyopathies. Author summary The human genetic code is highly preserved, yet RNA editing is a process that changes it in RNA molecules. This may alter the resultant proteins or the properties of the RNA strands themselves, leading to changes in their special structure and affecting their interaction with the immune system. Unedited RNA may be highly immunogenic, and studies of recent years demonstrated that dysregulated editing causes an inflammatory response. We show that human RNA editing is especially active in the arteries and investigate its role in cardiovascular diseases such as atherosclerosis and cardiomyopathies. These diseases have an underlying inflammatory component that eventually leads to the loss of normal structure and function. We show that RNA editing is increased in patients and draw a line connecting it with a concomitant increase in inflammatory pathways. We also detected specific coding editing sites, mainly in the IGFBP7 gene, where aberrant editing is present, resulting in an altered protein product. We delineate these changes and suggest they may contribute to or are a marker of the underlying pathology. Our findings indicate that RNA editing is a key player in several cardiovascular diseases.