Novel methodologies for biomarker discovery in atherosclerosis

Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging −omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma-derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk predictio

J Clin Invest

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPN). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPN suggests that vascular function is altered. Consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice, resulting from disturbed endothelial nitric oxide pathway and increased endothelial oxidative stress. This response was reproduced in wild-type mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for microvesicles effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes supressed their effect on oxidative stress. Antioxidants, such as simvastatin and N-acetyl-cysteine, improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPN are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears as promising therapeutic strategy in this setting

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology

Microvesicles are members of the family of extracellular vesicles shed from the plasma membrane of activated or apoptotic cells. Microvesicles were initially characterised by their pro-coagulant activity and described as "microparticles". There is mounting evidence revealing a role for microvesicles in intercellular communication, with particular relevance to hemostasis and vascular biology. Coupled with this, the potential of microvesicles as meaningful biomarkers is under intense investigation. This Position Paper will summarise the current knowledge on the mechanisms of formation and composition of microvesicles of endothelial, platelet, red blood cell and leukocyte origin. This paper will also review and discuss the different methods used for their analysis and quantification, will underline the potential biological roles of these vesicles with respect to vascular homeostasis and thrombosis and define important themes for future research

Microparticules endothéliales circulantes et dysfonction endothéliale in vivo

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Rôle des microparticules de plaque d'athérosclérose humaine dans le développement de l'athérothrombose

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Expression et fonction de la NOS neuronale dans les cellules musculaires lisses de la paroi vasculaire

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF