Publications
217 results found
Scott A, Ballesteros LS, Bradshaw M, et al., 2021, In Vivo Characterization of Endogenous Cardiovascular Extracellular Vesicles in Larval and Adult Zebrafish, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 41, Pages: 2454-2468, ISSN: 1079-5642
Abdulrazzak H, Ruiz-Lozano P, Emanueli C, 2021, Epicardium-derived extracellular vesicles: a promising avenue for cardiac regeneration., Cardiovasc Res
Aday S, Hazan-Halevy I, Chamorro-Jorganes A, et al., 2021, Bioinspired artificial exosomes based on lipid nanoparticles carrying let-7b-5p promote angiogenesis in vitro and in vivo, Molecular Therapy, Vol: 29, Pages: 2239-2252, ISSN: 1525-0016
MicroRNAs (miRNAs) regulate gene expression by post-transcriptional inhibition of target genes. Proangiogenic small extracellular vesicles (sEVs; popularly identified with the name "exosomes") with a composite cargo of miRNAs are secreted by cultured stem cells and present in human biological fluids. Lipid nanoparticles (LNPs) represent an advanced platform for clinically approved delivery of RNA therapeutics. In this study, we aimed to (1) identify the miRNAs responsible for sEV-induced angiogenesis; (2) develop the prototype of bioinspired "artificial exosomes" (AEs) combining LNPs with a proangiogenic miRNA, and (3) validate the angiogenic potential of the bioinspired AEs. We previously reported that human sEVs from bone marrow (BM)-CD34+ cells and pericardial fluid (PF) are proangiogenic. Here, we have shown that sEVs secreted from saphenous vein pericytes and BM mesenchymal stem cells also promote angiogenesis. Analysis of miRNA datasets available in-house or datamined from GEO identified the let-7 family as common miRNA signature of the proangiogenic sEVs. LNPs with either hsa-let-7b-5p or cyanine 5 (Cy5)-conjugated Caenorhabditis elegans miR-39 (Cy5-cel-miR-39; control miRNA) were prepared using microfluidic micromixing. let-7b-5p-AEs did not cause toxicity and transferred functionally active let-7b-5p to recipient endothelial cells (ECs). let-7b-AEs also improved EC survival under hypoxia and angiogenesis in vitro and in vivo. Bioinspired proangiogenic AEs could be further developed into innovative nanomedicine products targeting ischemic diseases.
Badimon L, Robinson EL, Jusic A, et al., 2021, Cardiovascular RNA markers and artificial intelligence may improve COVID-19 outcome: a position paper from the EU-CardioRNA COST Action CA17129., Cardiovasc Res, Vol: 117, Pages: 1823-1840
The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of 8 February 2020 and causing more than 2.3 million deaths according to the World Health Organization (WHO). Not only affecting the lungs but also provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events, such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast-track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision-making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation, and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts, and the added value of artificial intelligence to achieve reliable advances.
Robinson EL, Emanueli C, Martelli F, et al., 2021, Leveraging non-coding RNAs to fight cardiovascular disease: the EU-CardioRNA network., Eur Heart J
Chamorro-Jorganes A, Sweaad WK, Katare R, et al., 2021, METTL3 Regulates Angiogenesis by Modulating let-7e-5p and miRNA-18a-5p Expression in Endothelial Cells, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 41, Pages: E325-E337, ISSN: 1079-5642
Sweaad WK, Stefanizzi FM, Chamorro-Jorganes A, et al., 2021, Relevance of N6-methyladenosine regulators for transcriptome: Implications for development and the cardiovascular system., J Mol Cell Cardiol, Vol: 160, Pages: 56-70
N6-methyladenosine (m6A) is the most abundant and well-studied internal modification of messenger RNAs among the various RNA modifications in eukaryotic cells. Moreover, it is increasingly recognized to regulate non-coding RNAs. The dynamic and reversible nature of m6A is ensured by the precise and coordinated activity of specific proteins able to insert ("write"), bind ("read") or remove ("erase") the m6A modification from coding and non-coding RNA molecules. Mounting evidence suggests a pivotal role for m6A in prenatal and postnatal development and cardiovascular pathophysiology. In the present review we summarise and discuss the major functions played by m6A RNA methylation and its components particularly referring to the cardiovascular system. We present the methods used to study m6A and the most abundantly methylated RNA molecules. Finally, we highlight the possible involvement of the m6A mark in cardiovascular disease as well as the need for further studies to better describe the mechanisms of action and the potential therapeutic role of this RNA modification.
Robinson EL, Baker AH, Brittan M, et al., 2021, Dissecting the transcriptome in cardiovascular disease., Cardiovasc Res
The human transcriptome comprises a complex network of coding and non-coding RNAs implicated in a myriad of biological functions. Non-coding RNAs exhibit highly organised spatial and temporal expression patterns and are emerging as critical regulators of differentiation, homeostasis and pathological states, including in the cardiovascular system. This review defines the current knowledge gaps, unmet methodological needs and describes the challenges in dissecting and understanding the role and regulation of the non-coding transcriptome in cardiovascular disease. These challenges include poor annotation of the non-coding genome, determination of the cellular distribution of transcripts, assessment of the role of RNA processing and identification of cell-type specific changes in cardiovascular physiology and disease. We highlight similarities and differences in the hurdles associated with the analysis of the non-coding and protein-coding transcriptomes. In addition, we discuss how the lack of consensus and absence of standardised methods affect reproducibility of data. These shortcomings should be defeated in order to make significant scientific progress and foster the development of clinically applicable non-coding RNA-based therapeutic strategies to lessen the burden of cardiovascular disease.
Bollini S, Emanueli C, 2021, To serve and protect: a new heart patrolling and recycling role for macrophages, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: E17-E20, ISSN: 0008-6363
Moscarelli M, Angelini GD, Emanueli C, et al., 2021, Remote ischemic preconditioning in isolated valve intervention. A pooled meta-analysis, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 324, Pages: 146-151, ISSN: 0167-5273
Greco S, Made A, Gaetano C, et al., 2020, Noncoding RNAs implication in cardiovascular diseases in the COVID-19 era, JOURNAL OF TRANSLATIONAL MEDICINE, Vol: 18
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- Citations: 3
Spencer HL, Sanders R, Boulberdaa M, et al., 2020, The LINC00961 transcript and its encoded micropeptide, small regulatory polypeptide of amino acid response, regulate endothelial cell function, CARDIOVASCULAR RESEARCH, Vol: 116, Pages: 1981-1994, ISSN: 0008-6363
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- Citations: 10
de Abreu RC, Fernandes H, Martins PADC, et al., 2020, Native and bioengineered extracellular vesicles for cardiovascular therapeutics, NATURE REVIEWS CARDIOLOGY, Vol: 17, Pages: 685-697, ISSN: 1759-5002
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- Citations: 25
Robinson EL, Gomes CPC, Potocnjak I, et al., 2020, A Year in the Life of the EU-CardioRNA COST Action: CA17129 Catalysing Transcriptomics Research in Cardiovascular Disease, NON-CODING RNA, Vol: 6
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- Citations: 2
Shearn AIU, Aday S, Ben-Aicha S, et al., 2020, Analysis of neat biofluids obtained during cardiac surgery using nanoparticle tracking analysis: methodological considerations, Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-14, ISSN: 2296-634X
Small extracellular vesicles (sEVs) are those nanovesicles 30–150 nm in size with a role in cell signalling and potential as biomarkers of disease. Nanoparticle tracking analysis (NTA) techniques are commonly used to measure sEV concentration in biofluids. However, this quantification technique can be susceptible to sample handing and machine settings. Moreover, some classes of lipoproteins are of similar sizes and could therefore confound sEV quantification, particularly in blood-derived preparations, such serum and plasma. Here we have provided methodological information on NTA measurements and systematically investigated potential factors that could interfere with the reliability and repeatability of results obtained when looking at neat biofluids (i.e., human serum and pericardial fluid) obtained from patients undergoing cardiac surgery and from healthy controls. Data suggest that variables that can affect vesicle quantification include the level of contamination from lipoproteins, number of sample freeze/thaw cycles, sample filtration, using saline-based diluents, video length and keeping the number of particles per frame within defined limits. Those parameters that are of less concern include focus, the “Maximum Jump” setting and the number of videos recorded. However, if these settings are clearly inappropriate the results obtained will be spurious. Similarly, good experimental practice suggests that multiple videos should be recorded. In conclusion, NTA is a perfectible, but still commonly used system for sEVs analyses. Provided users handle their samples with a highly robust and consistent protocol, and accurately report these aspects, they can obtain data that could potentially translate into new clinical biomarkers for diagnosis and monitoring of cardiovascular disease.
Emanueli C, Badimon L, Martelli F, et al., 2020, Call to action for the cardiovascular side of COVID-19 A call for cooperative action from the EU-CardioRNA COSTAction, EUROPEAN HEART JOURNAL, Vol: 41, Pages: 1796-1797, ISSN: 0195-668X
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- Citations: 6
Ozaki Tan SJ, Floriano JF, Nicastro L, et al., 2020, Novel Applications of Mesenchymal Stem Cell-Derived Exosomes for Myocardial Infarction Therapeutics, BIOMOLECULES, Vol: 10
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- Citations: 14
Stoica SC, Dorobantu DM, Vardeu A, et al., 2020, MicroRNAs as potential biomarkers in congenital heart surgery, JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, Vol: 159, Pages: 1532-+, ISSN: 0022-5223
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- Citations: 4
Tikhomirov R, Donnell BR-O, Catapano F, et al., 2020, Exosomes: From potential culprits to new therapeutic promise in the setting of cardiac fibrosis, Cells, Vol: 9, ISSN: 2073-4409
Fibrosis is a significant global health problem associated with many inflammatory and degenerative diseases affecting multiple organs, individually or simultaneously. Fibrosis develops when extracellular matrix (ECM) remodeling becomes excessive or uncontrolled and is associated with nearly all forms of heart disease. Cardiac fibroblasts and myofibroblasts are the main effectors of ECM deposition and scar formation. The heart is a complex multicellular organ, where the various resident cell types communicate between themselves and with cells of the blood and immune systems. Exosomes, which are small extracellular vesicles, (EVs), contribute to cell-to-cell communication and their pathophysiological relevance and therapeutic potential is emerging. Here, we will critically review the role of endogenous exosomes as possible fibrosis mediators and discuss the possibility of using stem cell-derived and/or engineered exosomes as anti-fibrotic agents.
Marchetti M, Meloni M, Anwar M, et al., 2020, MicroRNA-24-3p Targets Notch and Other Vascular Morphogens to Regulate Post-ischemic Microvascular Responses in Limb Muscles, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 21
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- Citations: 4
Floriano JF, Willis G, Catapano F, et al., 2020, Exosomes Could Offer New Options to Combat the Long-Term Complications Inflicted by Gestational Diabetes Mellitus, CELLS, Vol: 9
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- Citations: 6
Gomes CPDC, Schroen B, Kuster GM, et al., 2020, Regulatory RNAs in Heart Failure, CIRCULATION, Vol: 141, Pages: 313-328, ISSN: 0009-7322
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- Citations: 30
Vesentini G, Barbosa AMP, Damasceno DC, et al., 2020, Alterations in the structural characteristics of rectus abdominis muscles caused by diabetes and pregnancy: A comparative study of the rat model and women., PLoS One, Vol: 15
BACKGROUND AND OBJECTIVE: In the present study, we compared the effect of diabetic pregnancy on the rectus abdominis muscle (RAM) in humans and rats. We hypothesized that our animal model could provide valuable information about alterations in the RAM of women with Gestational Diabetes (GDM). METHOD: Newborns female rats (n = 10/group) were administered streptozotocin (100 mg/kg body weight) subcutaneously and were mated on reaching adulthood, to develop the mild hyperglycemic pregnant (MHP) rat model. At the end of pregnancy, the mothers were sacrificed, and the RAM tissue was collected. Pregnant women without GDM (non-GDM group; n = 10) and those diagnosed with GDM (GDM group; n = 8) and undergoing treatment were recruited, and RAM samples were obtained at C-section. The RAM architecture and the distribution of the fast and slow fibers and collagen were studied by immunohistochemistry. RESULTS: No statistically significant differences in the maternal and fetal characters were observed between the groups in both rats and women. However, significant changes in RAM architecture were observed. Diabetes in pregnancy increased the abundance of slow fibers and decreased fast fiber number and area in both rats and women. A decrease in collagen distribution was observed in GDM women; however, a similar change was not observed in the MHP rats. CONCLUSION: Our results indicated that pregnancy- associated diabetes- induced similar structural adaptations in the RAM of women and rats with slight alterations in fiber type number and area. These findings suggest that the MHP rat model can be used for studying the effects of pregnancy-associated diabetes on the fiber structure of RAM.
Chamorro-Jorganes A, Anwar M, Emanueli C, 2019, Changes in HDL-microRNA might create a lasting memory of high-fat diet, Cardiovascular Research, Vol: 116, Pages: 1237-1239, ISSN: 0008-6363
Chen H, Moreno-Moral A, Pesce F, et al., 2019, Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling, Nature Communications, Vol: 10, ISSN: 2041-1723
Chen H, Moreno-Moral A, Pesce F, et al., 2019, WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling, Nature Communications, Vol: 10, Pages: 1-19, ISSN: 2041-1723
Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
Machado MJC, Boardman R, Riu F, et al., 2019, Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia, MICROCIRCULATION, Vol: 26, ISSN: 1073-9688
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- Citations: 3
Dang Z, Avolio E, Albertario A, et al., 2019, Nerve growth factor gene therapy improves bone marrow sensory innervation and nociceptor-mediated stem cell release in a mouse model of type 1 diabetes with limb ischaemia, DIABETOLOGIA, Vol: 62, Pages: 1297-1311, ISSN: 0012-186X
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- Citations: 7
Gomes CPDC, Agg B, Andova A, et al., 2019, Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129, NON-CODING RNA, Vol: 5
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- Citations: 7
Besnier M, Shantikumar S, Anwar M, et al., 2019, miR-15a/-16 inhibit angiogenesis by targeting the Tie2 coding sequence: Therapeutic potential of a miR-15a/16 decoy system in limb ischemia., Molecular Therapy : Nucleic Acids, Vol: 17, Pages: 49-62, ISSN: 2162-2531
MicroRNA-15a (miR-15a) and miR-16, which are transcribed from the miR-15a/miR-16-1 cluster, inhibit post-ischemic angiogenesis. MicroRNA (miRNA) binding to mRNA coding sequences (CDSs) is a newly emerging mechanism of gene expression regulation. We aimed to (1) identify new mediators of the anti-angiogenic action of miR-15a and -16, (2) develop an adenovirus (Ad)-based miR-15a/16 decoy system carrying a luciferase reporter (Luc) to both sense and inhibit miR-15a/16 activity, and (3) investigate Ad.Luc-Decoy-15a/16 therapeutic potential in a mouse limb ischemia (LI) model. LI increased miR-15a and -16 expression in mouse muscular endothelial cells (ECs). The miRNAs also increased in cultured human umbilical vein ECs (HUVECs) exposed to serum starvation, but not hypoxia. Using bioinformatic tools and luciferase activity assays, we characterized miR-15a and -16 binding to Tie2 CDS. In HUVECs, miR-15a or -16 overexpression reduced Tie2 at the protein, but not the mRNA, level. Conversely, miR-15a or -16 inhibition improved angiogenesis in a Tie2-dependent manner. Local Ad.Luc-Decoy-15a/16 delivery increased Tie2 levels in ischemic skeletal muscle and improved post-LI angiogenesis and perfusion recovery, with reduced toe necrosis. Bioluminescent imaging (in vivo imaging system [IVIS]) provided evidence that the Ad.Luc-Decoy-15a/16 system responds to miR-15a/16 increases. In conclusion, we have provided novel mechanistic evidence of the therapeutic potential of local miR-15a/16 inhibition in LI.
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