Multiomics of Tissue Extracellular Vesicles Identifies Unique Modulators of Atherosclerosis and Calcific Aortic Valve Stenosis.

Humans Aortic Valve / pathology Aortic Valve Stenosis / pathology Multiomics Calcinosis / metabolism Cells, Cultured MicroRNAs / metabolism Atherosclerosis / pathology Wnt Signaling Pathway Extracellular Vesicles / metabolism
aortic valve stenosis atherosclerosis extracellular vesicles microRNAs proteomics

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
22 08 2023
Historique:
pmc-release: 22 08 2024
medline: 23 8 2023
pubmed: 10 7 2023
entrez: 10 7 2023
Statut: ppublish

Résumé

Fewer than 50% of patients who develop aortic valve calcification have concomitant atherosclerosis, implying differential pathogenesis. Although circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs are associated with early mineralization, but their cargoes, functions, and contributions to disease remain unknown. Disease stage-specific proteomics was performed on human carotid endarterectomy specimens (n=16) and stenotic aortic valves (n=18). Tissue EVs were isolated from human carotid arteries (normal, n=6; diseased, n=4) and aortic valves (normal, n=6; diseased, n=4) by enzymatic digestion, (ultra)centrifugation, and a 15-fraction density gradient validated by proteomics, CD63-immunogold electron microscopy, and nanoparticle tracking analysis. Vesiculomics, comprising vesicular proteomics and small RNA-sequencing, was conducted on tissue EVs. TargetScan identified microRNA targets. Pathway network analyses prioritized genes for validation in primary human carotid artery smooth muscle cells and aortic valvular interstitial cells. Disease progression drove significant convergence ( The first comparative proteomics study of human carotid artery plaques and calcified aortic valves identifies unique drivers of atherosclerosis versus aortic valve stenosis and implicates EVs in advanced cardiovascular calcification. We delineate a vesiculomics strategy to isolate, purify, and study protein and RNA cargoes from EVs entrapped in fibrocalcific tissues. Integration of vesicular proteomics and transcriptomics by network approaches revealed novel roles for tissue EVs in modulating cardiovascular disease.

Sections du résumé

BACKGROUND
Fewer than 50% of patients who develop aortic valve calcification have concomitant atherosclerosis, implying differential pathogenesis. Although circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs are associated with early mineralization, but their cargoes, functions, and contributions to disease remain unknown.
METHODS
Disease stage-specific proteomics was performed on human carotid endarterectomy specimens (n=16) and stenotic aortic valves (n=18). Tissue EVs were isolated from human carotid arteries (normal, n=6; diseased, n=4) and aortic valves (normal, n=6; diseased, n=4) by enzymatic digestion, (ultra)centrifugation, and a 15-fraction density gradient validated by proteomics, CD63-immunogold electron microscopy, and nanoparticle tracking analysis. Vesiculomics, comprising vesicular proteomics and small RNA-sequencing, was conducted on tissue EVs. TargetScan identified microRNA targets. Pathway network analyses prioritized genes for validation in primary human carotid artery smooth muscle cells and aortic valvular interstitial cells.
RESULTS
Disease progression drove significant convergence (
CONCLUSIONS
The first comparative proteomics study of human carotid artery plaques and calcified aortic valves identifies unique drivers of atherosclerosis versus aortic valve stenosis and implicates EVs in advanced cardiovascular calcification. We delineate a vesiculomics strategy to isolate, purify, and study protein and RNA cargoes from EVs entrapped in fibrocalcific tissues. Integration of vesicular proteomics and transcriptomics by network approaches revealed novel roles for tissue EVs in modulating cardiovascular disease.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.122.063402 PMID: 37427430 PMC: PMC10527599
pubmed: 37427430
doi: 10.1161/CIRCULATIONAHA.122.063402
pmc: PMC10527599
mid: NIHMS1911136
doi:

Substances chimiques

MicroRNAs 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

661-678

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL141917
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL150401
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136431
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002541
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134892
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL080472
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL149998
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147095
Pays : United States
Organisme : NHLBI NIH HHS
ID : K25 HL150336
Pays : United States

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Auteurs

Mark C Blaser (MC)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).
ORCID: 0000-0002-3923-9786

Fabrizio Buffolo (F)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).

Arda Halu (A)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).
Channing Division of Network Medicine, Department of Medicine (A.H., M.A.).
ORCID: 0000-0001-6217-790X

Mandy E Turner (ME)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).

Florian Schlotter (F)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).
ORCID: 0000-0003-4840-1172

Hideyuki Higashi (H)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).

Lorena Pantano (L)

T H Chan School of Public Health, Harvard University, Boston, MA (L.P.).
ORCID: 0000-0002-3859-3249

Cassandra L Clift (CL)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).
ORCID: 0000-0003-2441-4251

Louis A Saddic (LA)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).

Samantha K Atkins (SK)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).

Maximillian A Rogers (MA)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).

Tan Pham (T)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).

Amélie Vromman (A)

Channing Division of Network Medicine, Department of Medicine (A.H., M.A.).
ORCID: 0000-0002-1724-2095

Eugenia Shvartz (E)

Channing Division of Network Medicine, Department of Medicine (A.H., M.A.).

Galina K Sukhova (GK)

Channing Division of Network Medicine, Department of Medicine (A.H., M.A.).
ORCID: 0000-0002-1421-9455

Silvia Monticone (S)

Division of Internal Medicine and Hypertension (S.M.), University of Torino, Italy.
ORCID: 0000-0002-7322-2005

Giovanni Camussi (G)

Department of Medical Sciences (G.C.), University of Torino, Italy.

Simon C Robson (SC)

Center for Inflammation Research, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.C.R.).

Simon C Body (SC)

Boston University School of Medicine, Boston, MA (S.C.B.).
ORCID: 0000-0001-6721-7050

Jochen D Muehlschlegel (JD)

Center for Perioperative Genomics, Department of Anesthesiology, Perioperative and Pain Medicine (J.D.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Sasha A Singh (SA)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).
ORCID: 0000-0003-0929-3164

Masanori Aikawa (M)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).
Channing Division of Network Medicine, Department of Medicine (A.H., M.A.).
Center for Excellence in Vascular Biology, Cardiovascular Division, Department of Medicine (A.V., E.S., G.K.S., M.A., E.A.).
ORCID: 0000-0002-9275-2079

Elena Aikawa (E)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine (M.C.B., F.B., A.H., M.E.T., F.S., H.H., C.L.C., L.A.S., S.K.A., M.A.R., T.P., S.A.S., M.A., E.A.).
Center for Excellence in Vascular Biology, Cardiovascular Division, Department of Medicine (A.V., E.S., G.K.S., M.A., E.A.).
ORCID: 0000-0001-7835-2135

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Système cardiovasculaire › Coeur › Valves cardiaques › Valve aortique › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Obstacle à l'éjection ventriculaire › Sténose aortique › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Sciences de l'information › Informatique › Biologie informatique › Multi-omique › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles du métabolisme du calcium › Calcinose › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Cellules › Cellules cultivées › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › microARN › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Artériopathies oblitérantes › Artériosclérose › Athérosclérose › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Voie de signalisation Wnt › Multiomics of Tissue Extracellular Vesicles...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace extracellulaire › Vésicules extracellulaires › Multiomics of Tissue Extracellular Vesicles...