deciphering the RNA modification code
in cardiometabolic health and disease
RNA Modifications in Endothelial Innate Immune Responses and Atherosclerotic Vascular Disease
Our current research is focused on the elucidation of the role of biochemical RNA modifications in RNA metabolism of coding and non-coding RNAs in vascular and blood cells. We have recently reported that adenosine to inosine RNA editing of the Alu elements located within the 3'-untranslated region of cathepsin S mRNA controls cathepsin S mRNA stability by regulating the recruitment of the stabilising RNA-binding protein HuR (Nat Med. 2016; 22(10):1140-1150). This mechanism is induced under pro-inflammatory conditions and was found to be enhanced in patients with atherosclerosis.
Further studies of our lab are evaluating the role of RNA editing in the RNA metabolism of other coding as well as non-coding RNAs and its impact on cellular function and disease development. With the help of a broad spectrum of molecular and cell biology methodologies including next generation high throughput RNA sequencing, cloning/Sanger sequencing, RNA-immunoprecipitation, RNA biology assays and iCLIP studies we identify in a single-nucleotide resolution the impact of RNA modifications on RNA metabolism and RNA-protein interactions. Subsequently, we evaluate the role of RNA modification in cellular functions and stress responses.
The in vivo relevance of our findings is determined in mouse (disease) models using loxP-flanked and Cre-reporter mouse strains. Further, we evaluate the clinical relevance of our bench findings in cells and tissues derived from large cohorts of patients with subclinical atherosclerosis, stable coronary heart disease, acute myocardial infarction, carotid advanced atherosclerotic disease or aortic aneurysms.
Novel Biomarkers for Risk Stratification of Patients with Cardiovascular Disease
Understanding how environmental stress stimuli alter the RNA interactome and subsequently inflammation enables us to delineate the epitranscriptomic and molecular pathways that control gene expression and cellular function in homeostasis and disease. We use this knowledge to develop novel prognostic cardiovascular disease biomarkers or to devise pharmacologic and genetic therapies for cardiovascular disease in humans. In line with this, we have previously reported that in patients with stable coronary heart disease, blood levels of amyloid beta 1-40 peptide are associated with cardiovascular mortality and morbidity over 5 years, independent of conventional risk factors (J Am Coll Cardiol. 2015 Mar 10;65(9):904-16). Most importantly, we recently reported that baseline blood levels of amyloid beta 1-40 peptide predict mortality in patients with non-ST-segment elevation acute coronary syndrome and reclassify the patients to correct risk categories beyond the GRACE score (Ann Intern Med. 2018 May 22). These findings clearly demonstrate that the pro-inflammatory peptide amyloid beta 1-40 may serve as a prognostic biomarker of coronary heart disease.
We currently evaluate – in close collaboration with our associate clinical research group at the National and Kapodistrian University of Athens, Athens, Greece, (co-PI: Associate Prof. Kimon Stamatelopoulos) and many international partners in Europe and USA - the incremental value of novel disease biomarkers for risk stratification in general population (primary prevention) and in patients with cardiovascular disease (secondary prevention).