Imperial College London

ProfessorCostanzaEmanueli

Faculty of MedicineNational Heart & Lung Institute

Chair in Cardiovascular Science
 
 
 
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Contact

 

c.emanueli Website

 
 
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Location

 

434ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

189 results found

Chen H, Moreno-Moral A, Pesce F, Devapragash N, Mancini M, Heng EL, Rotival M, Srivastava PK, Harmston N, Shkura K, Rackham OJL, Yu W-P, Sun X-M, Tee NGZ, Tan ELS, Barton PJR, Felkin LE, Lara-Pezzi E, Angelini G, Beltrami C, Pravenec M, Schafer S, Bottolo L, Hubner N, Emanueli C, Cook SA, Petretto Eet al., 2019, Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling., Nat Commun, Vol: 10

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Journal article

Chen H, Moreno-Moral A, Pesce F, Devapragash N, Mancini M, Heng E, Rotival M, Srivastava P, Harmston N, Shkura K, Rackham O, Yu W-P, Sun X-M, Gui Zhen Tee N, Tan E, Barton P, Felkin L, Lara-Pezzi E, Angelini G, Beltrami C, Pravenec M, Schafer S, Bottolo L, Hubner N, Emanueli C, Cook S, Petretto Eet al., WWP2 regulates pathological cardiac fibrosis by modulating 2 SMAD2 signaling, Nature Communications, ISSN: 2041-1723

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases which causes cardiac electrical and pump failure. The transforming growth factor β (TGFβ)/SMAD signaling pathway plays a key role in driving cardiac fibrosis. However, while several intervention points within the TGFβ signaling have been proposed, efforts have not translated. Here, we employed 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, we found that the pro-fibrotic gene network regulated by WWP2 is conserved across different cardiac diseases characterized by fibrosis, namely human and murine dilated cardiomyopathy and in repaired tetralogy of Fallot. Transgenic mice lacking the N56 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, where they interact with SMAD2 promoting its monoubiquitination. This nuclear interaction mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2. These studies reveal a previously unappreciated role of WWP2 in pathological cardiac fibrosis and suggest WWP2 as a potential target for treating heart diseases

Journal article

Machado MJC, Boardman R, Riu F, Emanueli C, Benest AV, Bates DOet 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

INTRODUCTION: Arteriolargenesis can be induced by concomitant stimulation of nitric Oxide (NO)-Angiopoietin receptor (Tie)-Vascular Endothelial Growth Factor (VEGF) signaling in the rat mesentery angiogenesis assay. We hypothesized that the same combination of exogenously added growth factors would also have a positive impact on arteriolargenesis and, consequently, the recovery of blood flow in a model of unilateral hindlimb ischemia. RESULTS AND METHODS: NO-Tie mice had faster blood flow recovery compared to control mice, as assessed by laser speckle imaging. There was no change in capillary density within the ischemic muscles, but arteriole density was higher in NO-Tie mice. Given the previously documented beneficial effect of VEGF signaling, we tested whether NO-Tie-VEGF mice would show further improvement. Surprisingly, these mice recovered no differently from control, arteriole density was similar and capillary density was lower. Dll4 is a driver of arterial specification, so we hypothesized that Notch1 expression would be involved in arteriolargenesis. There was a significant upregulation of Notch1 transcripts in NO-Tie-VEGF compared with NO-Tie mice. Using soluble Dll4 (sDll4), we stimulated Notch signaling in the ischemic muscles of mice. NO-Tie-sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery. CONCLUSION: These results suggest that Dll4 activation early on in revascularization can lead to unproductive angiogenesis and arteriolargenesis, despite increased vascular densities. These results suggest spatial and temporal balance of growth factors needs to be perfected for ideal functional and anatomical revascularisation.

Journal article

Dang Z, Avolio E, Albertario A, Sala-Newby GB, Thomas AC, Wang N, Emanueli C, Madeddu Pet 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

Journal article

Gomes CPDC, Agg B, Andova A, Arslan S, Baker A, Bartekova M, Beis D, Betsou F, Wettinger SB, Bugarski B, Condorelli G, da Silva GJJ, Danilin S, de Gonzalo-Calvo D, Buil A, Carmo-Fonseca M, Enguita FJ, Felekkis K, Ferdinandy P, Gyoengyoesi M, Hackl M, Karaduzovic-Hadziabdic K, Hellemans J, Heymans S, Hlavackova M, Hoydal MA, Jankovic A, Jusic A, Kardassis D, Kerkela R, Kuster GM, Lakkisto P, Leszek P, Lustrek M, Maegdefessel L, Martelli F, Novella S, O'Brien T, Papaneophytou C, Pedrazzini T, Pinet F, Popescu O, Potocnjak I, Robinson E, Sasson S, Scholz M, Simionescu M, Stoll M, Varga ZV, Vinciguerra M, Xuereb A, Yilmaz MB, Emanueli C, Devaux Yet al., 2019, Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129, NON-CODING RNA, Vol: 5

Journal article

Besnier M, Shantikumar S, Anwar M, Dixit P, Chamorro-Jorganes A, Sweaad W, Sala-Newby G, Madeddu P, Thomas AC, Howard L, Mushtaq S, Petretto E, Caporali A, Emanueli Cet 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.

Journal article

Moscarelli M, Fiorentino F, Suleiman M-S, Emanueli C, Reeves BC, Punjabi PP, Angelini GDet al., 2019, Remote ischaemic preconditioning in isolated aortic valve and coronary artery bypass surgery: a randomized trial, EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY, Vol: 55, Pages: 905-912, ISSN: 1010-7940

Journal article

Stoica SC, Dorobantu DM, Vardeu A, Biglino G, Ford KL, Bruno DV, Zakkar M, Mumford A, Angelini GD, Caputo M, Emanueli Cet al., 2019, MicroRNAs as potential biomarkers in congenital heart surgery., J Thorac Cardiovasc Surg

OBJECTIVE: Pediatric congenital heart surgery (CHS) involves intracardiac, valvular, and vascular repairs. Accurate tools to aid short-term outcome prediction in pediatric CHS are lacking. Clinical scores, such as the vasoactive-inotrope score and ventilation index, are used to define outcome in clinical studies. MicroRNA-1-3p (miR-1) is expressed by both cardiomyocytes and vascular cells and is regulated by hypoxia. In adult patients, miR-1 increases in the circulation after open-heart cardiac surgery, suggesting its potential as a clinical biomarker. Thus, we investigated whether perioperative circulating miR-1 measurements can help predict post-CHS short-term outcomes in pediatric patients. METHODS: Plasma miR-1 was retrospectively measured in a cohort of 199 consecutive pediatric CHS patients (median age 1.2 years). Samples were taken before surgery and at the end of the operation. Plasma miR-1 concentration was measured by reverse transcription-quantitative polymerase chain reaction and expressed as miR-1 copies/μL and as relative expression to spiked-in exogenous cel-miR-39. RESULTS: Baseline plasma miR-1 did not vary across different diagnoses, increased during surgery (204-fold median relative increase, P < .001), and was associated with aortic crossclamp duration postoperatively (P < .001). Importantly, miR-1 levels at the end of the operation positively correlated with intensive care stay (P < .001), early severe cardiovascular events (P = .01), and with high vasoactive-inotrope score (P = .001) and ventilation index (P < .001), suggesting that miR-1 could accelerate the identification of patients with cardiopulmonary bypass-related ischemic complications, requiring more intensive support. CONCLUSIONS: Our study suggests miR-1 as a novel potential circulating biomarker to predict early postoperative outcome and inform clinical management in pediatric heart surgery.

Journal article

Sophocleous F, Biffi B, Milano EG, Bruse J, Caputo M, Rajakaruna C, Schievano S, Emanueli C, Bucciarelli-Ducci C, Biglino Get al., 2019, Aortic morphological variability in patients with bicuspid aortic valve and aortic coarctation, European Journal of Cardio-Thoracic Surgery, Vol: 55, Pages: 704-713, ISSN: 1010-7940

OBJECTIVES: This study aimed to explore aortic morphology and the associations between morphological features and cardiovascular function in a population of patients with bicuspid aortic valve, while further assessing differences between patients with repaired coarctation, patients with unrepaired coarctation and patients without coarctation. METHODS: This is a single-centre retrospective study that included patients with available cardiovascular magnetic resonance imaging data and native bicuspid aortic valve diagnosis (n = 525). A statistical shape analysis was performed on patients with a 3-dimensional magnetic imaging resonance (MRI) dataset (n = 108), deriving 3-dimensional aortic reconstructions and computing a mean aortic shape (template) for the whole population as well as for the 3 subgroups of interest (no coarctation, repaired coarctation and unrepaired coarctation). Shape deformations (modes) were computed and correlated with demographic variables, 2-dimensional MRI measurements and volumetric and functional data. RESULTS: Overall, the results showed that patients with coarctation tended towards a more Gothic arch architecture, with decreased ascending and increased descending aorta diameters, with the unrepaired-aortic coarctation subgroup exhibiting more ascending aorta dilation. Careful assessment of patients with repaired coarctation only revealed that a more Gothic arch, increased descending aorta dimensions and ascending aorta dilation were associated with reduced ejection fraction (P ≤ 0.04), increased end-diastolic volume (P ≤ 0.04) and increased ventricular mass (P ≤ 0.02), with arch morphology distinguishing patients with and without recoarctation (P = 0.05). CONCLUSIONS: A statistical shape modelling framework was applied to a bicuspid aortic valve population revealing nuanced differences in arch morphology and demonstrating that morphological features

Journal article

Ford KL, Anwar M, Heys R, Ahmed EM, Caputo M, Game L, Reeves BC, Punjabi PP, Angelini GD, Petretto E, Emanueli Cet al., 2019, Optimisation of laboratory methods for whole transcriptomic RNA analyses in human left ventricular biopsies and blood samples of clinical relevance, PLoS ONE, Vol: 14, ISSN: 1932-6203

This study aimed to optimise techniques for whole transcriptome and small RNA analyses on clinical tissue samples from patients with cardiovascular disease. Clinical samples often represent a particular challenge to extracting RNA of sufficient quality for robust RNA sequencing analysis, and due to availability, it is rarely possible to optimise techniques on the samples themselves. Therefore, we have used equivalent samples from pigs undergoing cardiopulmonary bypass surgery to test different protocols for optimal RNA extraction, and then validated the protocols in human samples. Here we present an assessment of the quality and quantity of RNA obtained using a variety of commercially-available RNA extraction kits on both left ventricular biopsies and blood plasma. RNA extraction from these samples presents different difficulties; left ventricular biopsies are small and fibrous, while blood plasma has a low RNA content. We have validated our optimised extraction techniques on human clinical samples collected as part of the ARCADIA (Association of non-coding RNAs with Coronary Artery Disease and type 2 Diabetes) cohort study, resulting in successful whole transcriptome and small RNA sequencing of human left ventricular tissue.

Journal article

Shanmuganathan M, Vughs J, Noseda M, Emanueli Cet al., 2018, Exosomes: Basic biology and technological advancements suggesting their potential as ischemic heart disease therapeutics, Frontiers in Physiology, Vol: 9, ISSN: 1664-042X

Exosomes are small nano-sized vesicles that deliver biologically active RNA molecules and proteins to recipient cells through binding, fusion or endocytosis. There is emerging evidence that endogenous exosomes released by cardiovascular cells and progenitor cells impact cell survival and proliferation, thus regulating angiogenesis, cardiac protection and repair. These cardioprotective and regenerative traits have the potential to translate in to novel therapeutic options for post-ischaemic cardiac regeneration, thus potentially delaying the progression to ischaemic heart failure. Cellular stressors influence exosomes' secretion and the molecular composition of the exosome cargo, thus impacting on the above processes. Evidences are emerging that loading of proteins and RNAs in the exosomes cargos can be manipulated. Similarly, manipulation of exosomes surface proteins' expression to target exosomes to specific cells and tissues is doable. In addition, nature-inspired synthetic exosomes can be assembled to deliver specific clues to the recipient cells, including proliferative and differentiation stimuli, or shed paracrine signals enabling to reconstructing the heart homeostatic micro-environment. This review will describe exosome biogenesis and emerging evidence of exosome-mediated regenerative cell-to-cell communications and will conclude discussing possibilities of using exosomes to treat ischemic heart disease.

Journal article

Descamps B, Saif J, Benest AV, Biglino G, Bates DO, Chamorro-Jorganes A, Emanueli Cet al., 2018, BDNF (brain-derived neurotrophic factor) promotes embryonic stem cells differentiation to endothelial cells via a molecular pathway, including microRNA-214, EZH2 (enhancer of zeste homolog 2), and eNOS (endothelial nitric oxide synthase), Arteriosclerosis, Thrombosis, and Vascular Biology, Vol: 38, Pages: 2117-2125, ISSN: 1079-5642

Objective—The NTs (neurotrophins), BDNF (brain-derived neurotrophic factor) and NT-3 promote vascular development and angiogenesis. This study investigated the contribution of endogenous NTs in embryonic stem cell (ESC) vascular differentiation and the potential of exogenous BDNF to improve the process of ESC differentiation to endothelial cells (ECs).Approach and Results—Mouse ESCs were differentiated into vascular cells using a 2-dimensional embryoid body (EB) model. Supplementation of either BDNF or NT-3 increased EC progenitors’ abundance at day 7 and enlarged the peripheral vascular plexus with ECs and SM22α+ (smooth muscle 22 alpha-positive) smooth muscle cells by day 13. Conversely, inhibition of either BDNF or NT-3 receptor signaling reduced ECs, without affecting smooth muscle cells spread. This suggests that during vascular development, endogenous NTs are especially relevant for endothelial differentiation. At mechanistic level, we have identified that BDNF-driven ESC-endothelial differentiation is mediated by a pathway encompassing the transcriptional repressor EZH2 (enhancer of zeste homolog 2), microRNA-214 (miR-214), and eNOS (endothelial nitric oxide synthase). It was known that eNOS, which is needed for endothelial differentiation, can be transcriptionally repressed by EZH2. In turn, miR-214 targets EZH2 for inhibition. We newly found that in ESC-ECs, BDNF increases miR-214 expression, reduces EZH2 occupancy of the eNOS promoter, and increases eNOS expression. Moreover, we found that NRP-1 (neuropilin 1), KDR (kinase insert domain receptor), and pCas130 (p130 Crk-associated substrate kinase), which reportedly induce definitive endothelial differentiation of pluripotent cells, were increased in BDNF-conditioned ESC-EC. Mechanistically, miR-214 mediated the BDNF-induced expressional changes, contributing to BDNF-driven endothelial differentiation. Finally, BDNF-conditioned ESC-ECs promoted angiogenesis in vitro and in vivo.Concl

Journal article

MacAskill MG, Saif J, Condie A, Jansen MA, MacGillivray TJ, Tavares AAS, Fleisinger L, Spencer HL, Besnier M, Martin E, Biglino G, Newby DE, Hadoke PWF, Mountford JC, Emanueli C, Baker AHet al., 2018, Robust revascularization in models of limb ischemia using a clinically translatable human stem cell-derived endothelial cell product, Molecular Therapy, Vol: 26, Pages: 1669-1684, ISSN: 1525-0016

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy.

Journal article

Besnier M, Gasparino S, Vono R, Sangalli E, Facoetti A, Bollati V, Cantone L, Zaccagnini G, Maimone B, Fuschi P, Da Silva D, Schiavulli M, Aday S, Caputo M, Madeddu P, Emanueli C, Martelli F, Spinetti Get al., 2018, miR-210 enhances the therapeutic potential of bone-marrow-derived circulating proangiogenic cells in the setting of limb ischemia, Molecular Therapy, Vol: 26, Pages: 1694-1705, ISSN: 1525-0016

Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood. miR-210 expression was modulated with either an inhibitory complementary oligonucleotide (anti-miR-210) or a miRNA mimic (pre-miR-210). Scramble and absence of transfection served as controls. As expected, hypoxia increased miR-210 in PACs. In vivo, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. In vitro, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and enhanced by pre-miR-210. Moreover, pre-miR-210 increased PAC adhesion to ECs and supported angiogenic responses in co-cultured ECs. These responses were not associated with changes in extracellular miR-210 and were abrogated by lentivirus-mediated EFNA3 overexpression. Finally, ex-vivo pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic neovascularization and blood flow recovery in an immunodeficient mouse limb ischemia model. In conclusion, miR-210 modulates PAC functions and improves their therapeutic potential in limb ischemia.

Journal article

Sophocleous F, Milano EG, Pontecorboli G, Chivasso P, Caputo M, Rajakaruna C, Bucciarelli-Ducci C, Emanueli C, Biglino Get al., 2018, Enlightening the Association between Bicuspid Aortic Valve and Aortopathy, JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE, Vol: 5, ISSN: 2308-3425

Journal article

Alvino VV, Fernandez-Jimenez R, Rodriguez-Arabaolaza I, Slater S, Mangialardi G, Avolio E, Spencer H, Culliford L, Hassan S, Sueiro Ballesteros L, Herman A, Ayaon-Albarran A, Galan-Arriola C, Sanchez-Gonzalez J, Hennessey H, Delmege C, Ascione R, Emanueli C, Angelini GD, Ibanez B, Madeddu Pet al., 2018, Transplantation of allogeneic pericytes improves myocardial vascularization and reduces interstitial fibrosis in a swine model of reperfused acute myocardial infarction, Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease, Vol: 7, ISSN: 2047-9980

BackgroundTransplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model.Methods and ResultsWe performed a blind, randomized, placebo‚Äźcontrolled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following in vitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone.ConclusionsImmunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements.

Journal article

MacAskill MG, Saif J, Condie A, Jansen MA, MacGillivray TJ, Tavares AS, Fleisinger L, Newby DE, Hadoke PW, Mountford JC, Emanueli C, Baker AHet al., 2017, GMP-Compatible hESC-EC Improve Blood Flow in Multiple Peripheral Ischemia Mouse Models, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Dorobantu DM, Stoica S, Vardeu A, Bruno D, Zakkar M, Mumford A, Angelini G, Caputo M, Emanueli Cet al., 2017, Potential of Circulating MicroRNA-1 as New Perioperative Biomarker of Short-Term Outcome After Pediatric Congenital Heart Surgery, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Aday S, Zoldan J, Besnier M, Carreto L, Saif J, Fernandes R, Santos T, Bernardino L, Langer R, Emanueli C, Ferreira Let al., 2017, Synthetic microparticles conjugated with VEGF(165) improve the survival of endothelial progenitor cells via microRNA-17 inhibition, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723

Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases. Poor survival and vascular engraftment rates of transplanted cells force them to work mainly via time-limited paracrine actions. Although several approaches, including the use of soluble vascular endothelial growth factor (sVEGF)—VEGF165, have been developed in the last 10 years to enhance cell survival, they showed limited efficacy. Here, we report a pro-survival approach based on VEGF-immobilized microparticles (VEGF-MPs). VEGF-MPs prolong VEGFR-2 and Akt phosphorylation in cord blood-derived late outgrowth endothelial progenitor cells (OEPCs). In vivo, OEPC aggregates containing VEGF-MPs show higher survival than those treated with sVEGF. Additionally, VEGF-MPs decrease miR-17 expression in OEPCs, thus increasing the expression of its target genes CDKN1A and ZNF652. The therapeutic effect of OEPCs is improved in vivo by inhibiting miR-17. Overall, our data show an experimental approach to improve therapeutic efficacy of proangiogenic cells for the treatment of ischemic diseases.

Journal article

Gomes CPC, Spencer H, Ford KL, Michel LYM, Baker AH, Emanueli C, Balligand J-L, Devaux Yet al., 2017, The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 8, Pages: 494-507, ISSN: 2162-2531

Journal article

Rodriguez Martinez A, Posma JM, Ayala R, Neves AL, Anwar M, Petretto E, Emanueli C, Gauguier D, Nicholson JK, Dumas Met al., 2017, MWASTools: an R/Bioconductor package for metabolome-wide association studies, Bioinformatics, Vol: 34, Pages: 890-892, ISSN: 1367-4803

Summary: MWASTools is an R package designed to provide an integrated pipeline to analyze metabonomic data in large-scale epidemiological studies. Key functionalities of our package include: quality control analysis; metabolome-wide association analysis using various models (partial correlations, generalized linear models); visualization of statistical outcomes; metabolite assignment using statistical total correlation spectroscopy (STOCSY); and biological interpretation of MWAS results.Availability: The MWASTools R package is implemented in R (version > =3.4) and is available from Bioconductor: https://bioconductor.org/packages/MWASTools/

Journal article

Dykes IM, Emanueli C, 2017, Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA, GENOMICS PROTEOMICS & BIOINFORMATICS, Vol: 15, Pages: 177-186, ISSN: 1672-0229

Journal article

Coumans FAW, Brisson AR, Buzas EI, Dignat-George F, Drees EEE, El-Andaloussi S, Emanueli C, Gasecka A, Hendrix A, Hill AF, Lacroix R, Lee Y, van Leeuwen TG, Mackman N, Maeger I, Nolan JP, van der Pol E, Pegtel DM, Sahoo S, Siljander PRM, Sturk G, de Wever O, Nieuwland Ret al., 2017, Methodological Guidelines to Study Extracellular Vesicles, CIRCULATION RESEARCH, Vol: 120, Pages: 1632-1648, ISSN: 0009-7330

Journal article

Dumas M-E, Emanueli C, 2017, Circulating MicroRNAs to Predict the Risk for Metabolic Diseases in the General Population?, Diabetes, Vol: 66, Pages: 565-567, ISSN: 0012-1797

Journal article

Beltrami C, Besnier M, Shantikumar S, Shearn AIU, Rajakaruna C, Laftah A, Sessa F, Spinetti G, Petretto E, Angelini GD, Emanueli Cet al., 2017, Human pericardial fluid contains exosomes enriched with cardiovascular-expressed microRNAs and promotes therapeutic angiogenesis, Molecular Therapy, Vol: 25, Pages: 679-693, ISSN: 1525-0016

The pericardial fluid (PF) is contained in the pericardial sac surrounding the heart. MicroRNA (miRNA) exchange via exosomes (endogenous nanoparticles) contributes to cell-to-cell communication. We investigated the hypotheses that the PF is enriched with miRNAs secreted by the heart and that it mediates vascular responses through exosome exchange of miRNAs. The study was developed using leftover material from aortic valve surgery. We found that in comparison with peripheral plasma, the PF contains exosomes enriched with miRNAs co-expressed in patients’ myocardium and vasculature. At a functional level, PF exosomes improved survival, proliferation, and networking of cultured endothelial cells (ECs) and restored the angiogenic capacity of ECs depleted (via Dicer silencing) of their endogenous miRNA content. Moreover, PF exosomes improved post-ischemic blood flow recovery and angiogenesis in mice. Mechanistically, (1) let-7b-5p is proangiogenic and inhibits its target gene, TGFBR1, in ECs; (2) PF exosomes transfer a functional let-7b-5p to ECs, thus reducing their TGFBR1 expression; and (3) let-7b-5p depletion in PF exosomes impairs the angiogenic response to these nanoparticles. Collectively, our data support the concept that PF exosomes orchestrate vascular repair via miRNA transfer.

Journal article

Biglino G, Caputo M, Rajakaruna C, Angelini G, van Rooji E, Emanueli Cet al., 2017, Modulating microRNAs in cardiac surgery patients: Novel therapeutic opportunities?, PHARMACOLOGY & THERAPEUTICS, Vol: 170, Pages: 192-204, ISSN: 0163-7258

Journal article

Sasso L, Hosamuddin H, Emanueli C, 2017, Extracellular vesicles at the cross-line between basic science and clinical needs, MICROCIRCULATION, Vol: 24, ISSN: 1073-9688

Journal article

Caporali A, Miscianinov V, Saif J, Emanueli Cet al., 2016, MicroRNA transport in cardiovascular complication of diabetes, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, Vol: 1861, Pages: 2111-2120, ISSN: 1388-1981

Journal article

Sahoo S, Emanueli C, 2016, Exosomes in Diabetic Cardiomyopathy: The Next-Generation Therapeutic Targets?, DIABETES, Vol: 65, Pages: 2829-2831, ISSN: 0012-1797

Journal article

Fortunato TM, Beltrami C, Emanueli C, De Bank PA, Pula Get al., 2016, Platelet lysate gel and endothelial progenitors stimulate microvascular network formation in vitro: tissue engineering implications, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322

Journal article

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