Recognizing young investigators at Frontiers in Cardiovascular Biology 2018

Dr Heather Y. Small, BSc(Hons) MRes PhD is Senior Managing Editor of Cardiovascular Research. She is based in the Journal’s Editorial Office within the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, UK. The Frontiers in CardioVascular Biology Meeting 2018 was held in Vienna, Austria on 20th to 22nd April.1 One of the central aims of the meeting was to provide young investigators with a platform to disseminate their research and interact with world-leaders in the cardiovascular field.2 An example of such an initiative was the Young Investigators Award session. Finalists were selected from more than 500 abstracts for oral presentation and presented their research in two sessions, specialized into Cardiac and Vascular Biology. The two sessions had a truly international flair bringing together 12 presenters from 10 countries. Cardiovascular Research Onlife was present during the session and had the opportunity to talk to some of the young investigators about their work. To find out more about the benefits for young investigators for attending the FCVB meeting, watch our interview with conference organiser Professor Johan Wojta here: http://www.youtube.com/watch?v=MGWCGnkLoCg. Non-coding RNAs, including microRNAs (miRNAs), play an established role in the regulation of vascular biology at a molecular level.3,4 Tissue non-coding RNA profiles can be changed on a global scale in the setting of cardiovascular pathology.5 Soumaya Ben-Aicha Gonzalez, University of Barcelona, presented one such example of this in a pig model of diet-induced hypercholesterolaemia (HC). Soumaya identified a unique high-density lipoprotein (HDL)-miRNA profile, including increased miR-126-3p/5p in HC animals. In vitro studies demonstrated that endothelial cells contained three-fold greater expression miR-126-3p/5p when treated with HC versus normocholesterolemic HDL particles. Soumaya added that the forthcoming challenge would lay in validating the downstream targets of miR-126-3p/5p in endothelial cells and the mechanistic dissection of this miRNA’s effects on vascular function. Trafficking and delivery of miRNAs can also occur via extracellular vesicles (EVs).6 Data presented by Dr Alessandro Albini showed that miR-324-3p was significantly downregulated in plasma EVs from people with systemic sclerosis (SSc) and established pulmonary vascular disease relative to those with SSc only. In silico analysis suggested that miR-324-3p-targeted genes in relevant cell metabolism pathways; however, similar to Soumaya’s study, the key challenges will arise when investigating the downstream mechanism. RNA therapeutics are an emerging field of research with great potential for the cardiovascular field.3,7,8 RNA editing, in particular through the deamination of adenosine to inosine (A-to-I), is a recent addition to the RNA therapeutics toolkit. Aikaterini Gatsiou, Goethe University Frankfurt, demonstrated that double-stranded RNA-specific adenosine deaminase, a key enzyme involved in A-to-I editing, post-transcriptionally regulates a group of non-coding and coding inflammatory genes. This led to the control of leukocyte trafficking to inflamed tissues, including the endothelium; a central process in cardiovascular disease.9 Aikaterini added that narrowing down a specific pathological mechanism involving this pleiotropic enzyme was a central challenge to the study. Also focussed on RNA editing, Reginald van der Kwast, Leiden University Medical Centre, presented his findings that showed A-to-I editing of miRNA-487b altered the miRNA’s seed sequence. In turn, this changed target gene selection and promoted neovascularization after ischaemia. Reginald stated that the largest hurdle to overcome in this study was to devise and test ways to reliably quantify unedited versus edited miRNA transcripts since RNA editing was a relatively young field of research. These novel concepts regarding non-coding RNA regulation and function provide fresh potential for these molecules as biomarkers and therapies, which thus far have rarely translated into clinical benefit.10 Rosaria Bianco, University of Bristol, presented the results of a model in which to study the mechanisms of aneurysm formation and progression11 using arteries dissected from human umbilical cords. This human model has shown promising similarities to the existing pre-clinical mouse model of choice. In one such mouse model, Assistant Professor Aleksandra Piechota-Polanczyk of Jagiellonian University, showed that abdominal aortic aneurysms were twice as prevalent in a genetic mouse model lacking the master transcription factor nuclear factor erythroid 2-related factor 2. This was associated with changes in genes related to oxidative stress rather than inflammation. Congratulations to Aleksandra Piechota-Polanczyk! The miRNA theme continued into the Cardiac Biology session. Jason Karsheng Lew (University of Otago) presented an example of an environmental stimulus, high intensity interval exercise, altering miRNA expression in a mouse model of diabetes. Exercise significantly increased the expression of two cardiac-enriched miRNAs (miR-133a and miR-499) relative to the control group. These changes were associated with alterations in target gene expression and an improvement in pathological cardiac remodelling associated with diabetes. Moving forward, Jason said that he hopes to use a miRNA sponge approach12 to investigate directly the role of miR-133a and miR-499 in exercise-induced cardio-protection. Wajihah Mughal, University of Manitoba, also highlighted miR-133a expression in a different context as part of a vital necrosis pathway involved in cardiomyocyte differentiation and cardiac development. Knockdown of the molecule myocardin in ventricular cardiomyocytes led to a reduction in miR-133a expression triggering a molecular mechanism that resulted in a downstream accumulation of calcium in the mitochondria and cell death. Overexpression of miR-133a in vitro rescued this phenotype. Wajihah added that there were some technical hurdles to be overcome in interrogating this mechanism at a cellular level; in particular, she highlighted the importance of measuring necrosis versus apoptosis and the development of a delivery system for a fluorescent calcium biosensor that worked in subcellular compartments. With the goal of exploiting the delivery of miRNAs as a method of gene therapy, Elena Guzzolino of Consiglio Nazionale delle Ricerche, presented findings regarding miR-182, which is negatively regulated by TBX5. Mutations in the TBX5 gene are causative of Holt-Oram syndrome (HOS) in humans and have been implicated in early-onset atrial fibrillation.13 The depletion of TBX5 in the HOS murine model caused the overexpression of miR-182. Stable overexpression of miR-182 in a zebrafish model induced similar cardiac pathology to that observed in HOS. Elena was positive about the potential for miR-182 as a potential pathway to develop novel therapeutics; however, she hypothesised that several miRNAs would need to be targeted in one therapeutic approach owing to the increasing evidence of cross-regulation between transcription factors and miRNAs in the heart.14 Luca Braga, International Centre for Genetic Engineering and Biotechnology Trieste, presented his findings concerning a virus-mediated gene therapy approach to deliver miR-665 to a mouse model of Heart Failure with a Preserved Ejection Fraction (HFpEF). Mice treated with miR-665 showed an improvement in cardiac function; these findings add to the body of work that supports a role for miRNAs in HFpEF.15 Aleksandr Khudiakov, a Research Fellow at Almazov National Medical Research Centre, presented a pathological mechanism in arrhythmogenic cardiomyopathy that involved the dysregulation of the fine-tuned interplay between the desmosomal protein Plakophilin-2, the GSK3β signalling pathways and sodium channels—modelled using induced pluripotent stem cell-derived cardiomyocytes.16 Aleksandr stated that GSK3β inhibitors already existed for the treatment of neurological disease and that the work of himself and others in pre-clinical models provided a platform for repurposing this class of drugs for treating ACM. Markus Räsänen, University of Helsinki, alternatively used an in vivo approach to dissect out a novel mechanism in cardiomyocytes by generating a transgenic mouse model expressing VEGF-B under two different promoters that caused expression of VEGF-B in the coronary vascular endothelium and the cardiomyocytes, respectively. When VEGF-B was over-expressed in the endothelium, the mice exhibited pathological hypertrophy; however, VEGF-B over-expression in the cardiomyocytes resulted in physiological hypertrophy akin to that seen in athletes. Further investigation of these two models may result in new therapeutic pathways for heart failure. Congratulations to Luca Braga! See you all again at FCVB 2020 in Budapest, Hungary! Conflict of interest: none declared.