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MicroRNAs regulating cardiovascular functions: Frontiers in CardioVascular Biology 2012

Report from the Working Group on Thrombosis by Agneta Siegbahn

In recent years a small group of non-coding RNA called microRNAs (miRNAs) have emerged as important regulator of gene expression. These miRNAs are found to have important roles in various physiological and pathological processes such as cell differentiation, development and maintenance of tissue homeostasis. MiRNA have also been shown to play roles in many diseases and their presence in various tissues in the body and as in body fluids, most importantly in plasma, makes them high contenders as potential biomarkers of cardiovascular disease. The number of abstracts and selected talks presented at the second meeting of the ESC Council on Basic Cardiovascular Science in London ‘Frontiers in Cardio Vascular Biology’, clearly reflects the interest in this relatively new and upcoming area of research.

The difficult task is connecting an up- or down regulation of a particular miRNA transcript to a biological function or as causative of disease. Out of the many abstracts, the work presented by Gambacciani and collegues in Poster number 274 is a fine example showing how down regulation of two miRNA transcripts are linked to epigenetic reprogramming of gene expression. They showed in an in vitro assay how miR-29 and miR-30 directly interacts with the chromatin modifying enzyme DNMT3a. Furthermore, using a rat model of myocardial infarction they found that the levels of these two miRNAs were down regulated in ischemic tissue whilst the protein levels of DNMT3a were increased, not seen in healthy tissue. This is indicative of their role in epigenetic reprogramming of gene expression in the ischemic tissue.

Daimi and collegues also presented some interesting work in Poster number 324 whereby they connect the misregulation of a particular miRNA species to an altered biological function. This alteration in turn leads to a pathological condition and finally they explore the use of miRNAs as potential therapeutic agents. Performing functional studies in the cardiomyocyte celline, HL1, and using a luciferase reporter assay, they show that the up regulation of the miR-219 transcript is linked to an increase in SCN5A gene expression levels. SCN5A in turn codes for the Nav1.5 protein, a Na+ channel in the cell membrane involved in regulating normal cardiac rhythm. They noted using fluorescence microscopy how up regulation of SCN5a resulted in both a mislocalisation of the Nav1.5 protein to the endoplasmatic reticulum, as well as an altered cardiac rhythm in the HL1 cardiomyocytes. Using chimeric miR-219 transcripts they could show their role in modulating the stability of the SCN5A transcript resulting in the increase in Nav1.5 production, also seen in their in vivo mouse model. In humans, the therapeutic drug flexaine used to stabilise arrythmias has the side effect of easily causing flecaine intoxication. When miR-219 was injected into the mice they found that the overexpression rescued the mice from flecaine intoxication, although they found no effect on the heart rhythm. Albeit this shown that perhaps in a not too distant future miRNAs can be useful therapeutics, either on their own or in conjuction with traditional treatment methods to ameliorate side effects.

Macrophages under stress. Showcase: European Atherosclerosis Society.

The session entitled “Macrophages under stress” took place on Saturday 31 March and was chaired by Professor Frederic Geissmann from King’s college, London and Professor Johannes Waltenberger from Münster University.
The emerging role of the macrophage in health and disease was discussed, in particular macrophage polarisation and its implications for atherosclerosis and cancer. As was elaborated on by the different speakers during the symposium, macrophages may apart from its characteristic role as a scavenger and pro-inflammatory antigen-presenting cell also develop into so called alternatively polarised or M2 macrophages. These M2 macrophages have a pro-angiogenic and immuno-modulatory effect and contribute to resolution of inflammation during physiological conditions. While classically activated macrophages are well known to contribute to the development of atherosclerotic plaques, M2 macrophages are believed posses an atheroprotective effect through their immuno-modulatory properties.

In the opening talk of the session Dr Kristiaan Wouters from Maastricht University presented data on a newly discovered role for the p16INK4a tumor suppressor in macrophage polarisation. Through the use of a p16INK4a knock-out mouse model, it was showed that p16INK4a deficiency resulted in attenuated pro-inflammatory signalling in macrophages and increased propensity towards an IL4-induced M2 phenotype.
Next Professor Claire Lewis from University of Sheffield gave an overview over macrophage behaviour during hypoxia from an oncologist’s point of view. Professor Lewis introduced the concept of TAMs, tumor-associated macrophages, which are recruited to tumors and become alternatively polarised as a consequence of the tumor microenvironment. Macrophages in hypoxic areas up-regulate pro-angiogenic growth factors to increase tumor angiogenesis and secrete immunosuppressive cytokines to contribute to evasion from anti-tumor immunity. Thus the alternatively polarised macrophage plays a different role in cancer and may actually promote tumor progression.
Dr Stephanie Potteaux from INSERM in Paris continued to describe her work on the ApoE-/- mouse model, where restoration of ApoE expression was shown to reduce monocyte recruitment to atherosclerotic plaques. The author concluded that suppression of monocyte recruitment to plaques should be considered a therapeutic strategy for atherosclerosis.
The session was ended by two abstract presenters. Dr Seneviratne from Imperial College, London, talked about macrophage behaviour in atherosclerotic plaques during different shear stress conditions, and Dr Everaert from University of Antwerp gave a presentation on circulating angiogenic cells (CACs), a macrophage subtype.

Tissue factor in atherothrombosis – New aspects. Showcase for the Working Group on Thrombosis.

The session was held on Sunday 01 April and was chaired by professors Lina Badimon, Barcelona, Spain, and Agneta Siegbahn, Uppsala, Sweden. Tissue factor is a 47 kDa transmembrane glycoprotein and the principal initiator of coagulation. Exposure of surface bound TF to the blood results in the formation of the binary TF/FVIIa and the ternary TF/FVIIa/FXa complexes resulting in both fibrin deposition as well as intracellular signalling. Aberrant expression of TF is closely correlated to thrombotic events but also its non-coagulant signal transduction pathways are of importance for the development of atherosclerosis and as a driver of inflammation. The first speaker, Dr. Gemma Vilahur from the Catalan Institute of Cardiovascular Sciences in Barcelona, gave a talk on the subject Tissue factor in atherosclerotic lesion remodeling. Vascular remodeling confers to a change in the arterial size which is proportional to the plaque burden, important for maintaining the blood flow in e.g. coronary arteries. Dr. Vilahur presented data describing how smooth muscle cells migrate towards inflammatory cytokines in a TF-dependent manner, and discussed the positioning of TF within the migrating cell. By fluorescently labeling TF, she could convincingly show how TF redistributes to the leading edge of moving cells adding proof of TF´s role in cell migration. The next speaker, Dr. Mikael Åberg from Uppsala University in Sweden, further discussed the signalling aspects of the TF in his presentation Tissue factor / factor VIIa non-coagulant signalling couples coagulation and inflammation. He first stated that TF mRNA and protein expression was found within the atherosclerotic plaque in 1989 and that TF both induces and is induced by inflammatory cytokines, and thus couples coagulation and inflammation processes. The concept of non-coagulant signalling, i.e. signalling by the TF-complexes alone or via protease activated receptors (PARs) and not by downstream proteins e.g. thrombin, was also presented and examples of the practical consequences was given regarding migration and increased permeability of blood vessels. Studies on different types of cells suggest that cell-surface TF can be present in a functionally latent form (encrypted or cryptic TF), despite a correct insertion into the plasma membrane with an ability to bind factor VIIa. The final speaker, prof. Bernd Engelmann from the University of Munchen, described in his talk Protein disulfide isomerase in the regulation of TF activity how the thiol isomerase protein disulfide isomerase (PDI) is suggested to act as an injury response signal to enhance fibrin generation via TF activation. The mechanism was explained by a rapid oxidation of the Cys186-Cys209 pair by PDI in the membrane-proximal region of the extracellular domain of TF and present in both mouse models and human monocytes.