@article{cfe621ffb7a64e6f9cd9d57dd819f70e,
title = "RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction",
abstract = "Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE-/- mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticlebased RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)-targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrixdegrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI.",
author = "Sager, {Hendrik B.} and Partha Dutta and Dahlman, {James E.} and Maarten Hulsmans and Gabriel Courties and Yuan Sun and Timo Heidt and Claudio Vinegoni and Anna Borodovsky and Kevin Fitzgerald and Wojtkiewicz, {Gregory R.} and Yoshiko Iwamoto and Benoit Tricot and Khan, {Omar F.} and Kauffman, {Kevin J.} and Yiping Xing and Shaw, {Taylor E.} and Peter Libby and Robert Langer and Ralph Weissleder and Swirski, {Filip K.} and Anderson, {Daniel G.} and Matthias Nahrendorf",
note = "Funding Information: We thank M. Weglarz, K. Folz-Donahue, and L. Prickett-Rice from the Flow Cytometry Core Facility, MGH, Center for Regenerative Medicine and Harvard Stem Cell Institute, and M. Waring and A. Chicoine from Ragon Institute (MGH, Massachusetts Institute of Technology, and Harvard) for assistance with cell sorting; M. Sebas (MGH) for help with mouse surgery; and L. Altstein (biostatistician; MGH Biostatistics Center) for help with statistics. Funding: This work was funded by grants from the NIH (HL114477, HL117829, HL096576, and K99-HL121076), the MGH Research Scholar Award, and Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Award UL1 TR001102). H.B.S. and T.H. were funded by Deutsche Forschungsgemeinschaft (SA1668/2-1 and HE-6382/1-1). Author contributions: H.B.S., P.D., and J.E.D. designed and performed mouse experiments, flow cytometry, histology, qPCR, enzyme-linked immunosorbent assay, and particle and siRNA synthesis; collected and analyzed the data; and contributed to writing the article. M.H., G.C., Y.S., T.H., C.V., Y.I., O.F.K., K.J.K., Y.X., and T.E.S. performed mouse surgery, histology, and particle and siRNA synthesis. B.T. performed and analyzed cardiac MRI. G.R.W. performed and reconstructed FMT/CT and collected, analyzed, and discussed data. A.B., K.F., P.L., R.L., R.W., F.K.S., and D.G.A. conceived experiments and discussed strategy and results. M.N. designed and supervised the study and contributed to writing the article, which was edited and approved by all coauthors. Competing interests: J.E.D., D.G.A., and R.L. have filed intellectual property protection related to 7C1 nanoparticles. The authors declare that they have no further competing interests. Data and materials availability: Material transfer agreements may be required for nanoparticles.",
year = "2016",
month = jun,
day = "8",
doi = "10.1126/scitranslmed.aaf1435",
language = "English",
volume = "8",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "342",
}