title: E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis.
abstract: E-selectin is a surface marker of endothelial cell (EC) inflammation, one of the hallmarks of atherogenesis. Thus, we tested the hypothesis that delivery of microRNA (miR)-146a and miR-181b with an E-selectin-targeting multistage vector (ESTA-MSV) to inflamed endothelium covering atherosclerotic plaques inhibits atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and loaded into ESTA-MSV microparticles. Both miRs were downregulated in tumor necrosis factor (TNF)-α-treated ECs. Transfection of TNF-α-treated mouse aortas and cultured ECs with miRs was more efficient with ESTA-MSV than with the PEG/PEI. Likewise, miR-146a/-181b packaged in ESTA-MSV efficiently suppressed the chemokines, CCL2, CCL5, CCL8, and CXCL9, and monocyte adhesion to ECs. Complementary in vivo tests were conducted in male apolipoprotein E-deficient mice fed a Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Treatment with miRs packaged in ESTA-MSV but not in PEG/PEI reduced atherosclerotic plaque size. Concurrently, vascular inflammation markers, including macrophages in aortic root lesions and chemokine expression in aortic tissues were reduced while the vascular smooth muscle cells and collagen increased in plaques from ESTA-MSV/miRs-treated vs. vehicle-treated mice. Our data supported our hypothesis that ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates endothelial inflammation and atherosclerosis.
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Shuangtao
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.|Institute of Vascular Medicine, School of Biomedical Sciences and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Tian
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Yunrong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Mu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Methodist DeBakey Heart &Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Bismuth
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Pownall
authors.affiliation: Institute of Vascular Medicine, School of Biomedical Sciences and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Wing Tak
authors.initials: WT
authors.lastname: Wong
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage; D019040:E-Selectin / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage*; D058226:Plaque, Atherosclerotic / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D019040:E-Selectin; D035683:MicroRNAs