Inflammatory extracellular vesicles prompt heart dysfunction via TRL4-dependent NF-κB activation

Biemmi, Vanessa; Milano, Giuseppina; Ciullo, Alessandra; Cervio, Elisabetta; Burrello, Jacopo; Dei, Michele; Paroni, Rita; Tallone, Tiziano; Moccetti, Tiziano; Pedrazzini, Giovanni; Longnus, Sarah L.; Vassalli, Giuseppe; Barile, Lucio

doi:10.7150/thno.39072

Cited by 46 publications

(49 citation statements)

References 61 publications

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“…Although the consequences of having less Cx43 in ischemic EVs were not assessed in the present work, this may ultimately affect long-distance cell-cell communication. Grounded on our previous studies showing that EV-Cx43 facilitates the communication with acceptor cells and because post-infarction circulating EVs exacerbate inflammatory responses, contributing to impaired heart function, we can speculate that reduced Cx43 levels prevent the spreading of certain metabolites or signaling molecules, constituting a cardioprotective mechanism (Soares et al, 2015;Biemmi et al, 2020).…”

Section: Discussionmentioning

confidence: 89%

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

et al. 2020

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Ischemic heart disease has been associated with an impairment on intercellular communication mediated by both gap junctions and extracellular vesicles. We have previously shown that connexin 43 (Cx43), the main ventricular gap junction protein, assembles into channels at the extracellular vesicle surface, mediating the release of vesicle content into target cells. Here, using a comprehensive strategy that included cell-based approaches, animal models and human patients, we demonstrate that myocardial ischemia impairs the secretion of Cx43 into circulating, intracardiac and cardiomyocyte-derived vesicles. In addition, we show that ubiquitin signals Cx43 release in basal conditions but appears to be dispensable during ischemia, suggesting an interplay between ischemia-induced Cx43 degradation and secretion. Overall, this study constitutes a step forward for the characterization of the signals and molecular players underlying vesicle protein sorting, with strong implications on long-range intercellular communication, paving the way towards the development of innovative diagnostic and therapeutic strategies for cardiovascular disorders.

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Section: Discussionmentioning

confidence: 89%

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

et al. 2020

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“…Studies on murine models revealed that pharmacological inhibition of the synthesis of ceramides prevents heart failure after myocardial ischemia, decreasing ventricular remodeling, fibrosis, and inflammatory infiltrate 8,43,50 . Similarly, the administration of an inhibitor of neutral SMases which hydrolyzes sphingomyelin to ceramide, thus impairing EV biogenesis, namely GW4869, reduced the increase of circulating inflammatory EV after MI in rats, resulting in the preservation of left ventricular ejection fraction 27 .…”

Section: Discussionmentioning

confidence: 99%

“…All hemolytic plasma samples were excluded from the study. Free-platelet plasma was differentially centrifuged at 3000×g for 20 min to remove cellular debris, and then at 10,000×g for 30 min, and 20,000×g for 15 min to remove apoptotic bodies and large particles 27 . EV were obtained from 300uL of free-platelet plasma by ultracentrifugation at 100,000×g (18 h) using a Beckman Optima Max-TL ultracentrifuge (Beckman Coulter).…”

Section: Discussionmentioning

confidence: 99%

“…Protein concentrations were determined using BCA kit (Sigma). Equal amount of total proteins (30 μg) or equal volume of sample were boiled with Laemmli SDS sample buffer 6X (0.375 M Tris-HCl pH 6.8, 12% SDS, 60% glycerol, 0.6 M DTT, 20%(v/v) b-mercaptoethanol, 0.2% (w/v) bromophenol blue; VWR International), separated on 4-20% Mini-PROTEAN TGX Precast Gel (Bio-Rad), and transferred onto PVDF membranes with a semi-dry transfer system (Bio-Rad) 27 . The membranes were first blocked for 1 h in Odyssey Blocking Buffer (LI-COR Biosciences) diluted 1:1 in distilled water and supplemented with 0.2% Tween 20 (OBB-T), then incubated with the appropriate primary Ab diluted in OBB-T at 4 °C overnight under gentle agitation 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Progress has been made in obtaining lipoprotein-and albumin-free plasma EV via an iodixanol density gradient combined to bind elute chromatography (BEC) 25 , such technique is affected by limited yield 25 . In this study we employed UC isolation protocol to obtain plasma-derived EV in order to guarantee specificity without compromising yield 26 , while further optimizing the reduction of cross-contamination, as previously reported 27,28 .…”

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Sphingolipid composition of circulating extracellular vesicles after myocardial ischemia

Burrello

Biemmi

Dei

et al. 2020

Sci Rep

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Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling. Extracellular vesicles (EV) are lipid bilayer membrane nanoparticle and their lipid composition may be different from parental cells, with a significant enrichment in sphingolipid species, especially in pathological conditions. We aimed at optimizing EV isolation from plasma and describing the differential lipid content of EV, as compared to whole plasma. As pilot study, we evaluated the diagnostic potential of lipidomic signature of circulating EV in patients with a diagnosis of ST-segment-elevation myocardial infarction (STEMI). STEMI patients were evaluated before reperfusion and 24-h after primary percutaneous coronary intervention. Twenty sphingolipid species were quantified by liquid-chromatography tandem-mass-spectrometry. EV-ceramides, -dihydroceramides, and -sphingomyelins increased in STEMI vs. matched controls and decreased after reperfusion. Their levels correlated to hs-troponin, leucocyte count, and ejection fraction. Plasma sphingolipids levels were 500-to-700-fold higher as compared to EV content; nevertheless, only sphingomyelins differed in STEMI vs. control patients. Different sphingolipid species were enriched in EV and their linear combination by machine learning algorithms accurately classified STEMI patients at pre-PCI evaluation. In conclusion, EV lipid signature discriminates STEMI patients. These findings may contribute to the identification of novel biomarkers and signaling mechanisms related to cardiac ischemia.

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Cardiac remodelling – Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology

González

Richards

Boer

et al. 2022

European J of Heart Fail

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Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.

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Inflammatory extracellular vesicles prompt heart dysfunction via TRL4-dependent NF-κB activation

Cited by 46 publications

References 61 publications

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

Sphingolipid composition of circulating extracellular vesicles after myocardial ischemia

Cardiac remodelling – Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology

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