Conserved and Divergent Modulation of Calcification in Atherosclerosis and Aortic Valve Disease by Tissue Extracellular Vesicles

Blaser, M. C.; Buffolo, F.; Halu, A.; Schlotter, F.; Higashi, H.; Pantano, L.; Saddic, L. A.; Atkins, S. K.; Rogers, M. A.; Pham, T.; Shvartz, E.; Sukhova, G. K.; Monticone, S.; Camussi, G.; Body, S. C.; Muehlschlegel, J. D.; Singh, S. A.; Aikawa, M.; Aikawa, E.

doi:10.1101/2020.04.02.022525

bioRxiv · 10.1101/2020.04.02.022525

Conserved and Divergent Modulation of Calcification in Atherosclerosis and Aortic Valve Disease by Tissue Extracellular Vesicles

Blaser, M. C.·Buffolo, F.·Halu, A.·Schlotter, F.·Higashi, H.·Pantano, L.·Saddic, L. A.·Atkins, S. K.·Rogers, M. A.·Pham, T.·Shvartz, E.·Sukhova, G. K.·Monticone, S.·Camussi, G.·Body, S. C.·Muehlschlegel, J. D.·Singh, S. A.·Aikawa, M.·Aikawa, E.

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Abstract

BackgroundFewer than 50% of patients develop calcification of both atherosclerotic plaques and aortic valves, implying differential pathogenesis. While circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs associate with early mineralization, but their contents, function, and contributions to disease remain unknown. ResultsGlobal proteomics of human carotid artery endarterectomies and calcified aortic valves from a total of 27 donors/patients revealed significant over-representation of proteins with vesicle-associated pathways/ontologies common to both diseases. We exploited enzymatic digestion, serial (ultra)centrifugation and OptiPrep density-gradient separation to isolate EV populations from diseased arteries and valves. Mass spectrometry found 22 EV marker proteins to be highly enriched in the four least-dense OptiPrep fractions while extracellular matrix proteins predominated in denser fractions, as confirmed by CD63 immunogold electron microscopy and nanoparticle tracking analysis. Proteomics and miRNA-sequencing of OptiPrep-enriched tissue EVs quantified 1,104 proteins and 123 miR cargoes linked to 5,182 target genes. Pathway networks of proteins and miR targets common to artery and valve tissue EVs revealed a shared regulation of Rho GTPase and MAPK intracellular signaling cascades. 179 proteins and 5 miRs were significantly altered between artery and valve EVs; multi-omics integration determined that EVs differentially modulated cellular contraction and p53-mediated transcriptional regulation in diseased vascular vs. valvular tissue. ConclusionsOur findings delineate a strategy to isolate, purify, and study protein and RNA cargoes from EVs entrapped in fibrocalcific tissues. Multi-omics and network approaches implicated tissue-resident EVs in human cardiovascular disease.

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Blaser, M. C., Buffolo, F., Halu, A., Schlotter, F., Higashi, H., Pantano, L., Saddic, L. A., Atkins, S. K., Rogers, M. A., Pham, T., Shvartz, E., Sukhova, G. K., Monticone, S., Camussi, G., Body, S. C., Muehlschlegel, J. D., Singh, S. A., Aikawa, M., Aikawa, E.. 2020-04-03. Conserved and Divergent Modulation of Calcification in Atherosclerosis and Aortic Valve Disease by Tissue Extracellular Vesicles. https://doi.org/10.1101/2020.04.02.022525

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