title: Discovery of novel peptides targeting pro-atherogenic endothelium in disturbed flow regions -Targeted siRNA delivery to pro-atherogenic endothelium in vivo.
abstract: Atherosclerosis occurs preferentially in arterial regions exposed to disturbed blood flow. Targeting these pro-atherogenic regions is a potential anti-atherogenic therapeutic approach, but it has been extremely challenging. Here, using in vivo phage display approach and the partial carotid ligation model of flow-induced atherosclerosis in mouse, we identified novel peptides that specifically bind to endothelial cells (ECs) exposed to disturbed flow condition in pro-atherogenic regions. Two peptides, CLIRRTSIC and CPRRSHPIC, selectively bound to arterial ECs exposed to disturbed flow not only in the partially ligated carotids but also in the lesser curvature and branching point of the aortic arch in mice as well as human pulmonary artery branches. Peptides were conjugated to branched polyethylenimine-polyethylene glycol polymer to generate polyplexes carrying siRNA targeting intercellular adhesion molecule-1 (siICAM-1). In mouse model, CLIRRTSIC polyplexes carrying si-ICAM-1 specifically bound to endothelium in disturbed flow regions, reducing endothelial ICAM-1 expression. Mass spectrometry analysis revealed that non-muscle myosin heavy chain II A (NMHC IIA) is a protein targeted by CLIRRTSIC peptide. Further studies showed that shear stress regulates NMHC IIA expression and localization in ECs. The CLIRRTSIC is a novel peptide that could be used for targeted delivery of therapeutics such as siRNAs to pro-atherogenic endothelium.
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul,158-710, Republic of Korea.
authors.forename: Jihwa
authors.initials: J
authors.lastname: Chung
authors.affiliation: Departments of Bioinspired Science and Life Science, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoon-gu, Seoul, 120-750, Republic of Korea.
authors.forename: Hyunbo
authors.initials: H
authors.lastname: Shim
authors.affiliation: Department of Thoracic surgery, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea.
authors.forename: Kwanchang
authors.initials: K
authors.lastname: Kim
authors.affiliation: Center for Self-assembly and Complexity, Institute for Basic Science (IBS), and Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea.
authors.forename: Duhwan
authors.initials: D
authors.lastname: Lee
authors.affiliation: Center for Self-assembly and Complexity, Institute for Basic Science (IBS), and Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea.
authors.forename: Won Jong
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Life Science, College of Natural Science, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoon-gu, Seoul, 120-750, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kang
authors.affiliation: Department of Life Science, College of Natural Science, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoon-gu, Seoul, 120-750, Republic of Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul,158-710, Republic of Korea.|Department of Internal Medicine, Cardiology Division, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea.
authors.forename: Kihwan
authors.initials: K
authors.lastname: Kwon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000517:prevention & control*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018995:Myosin Heavy Chains / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: D010455:Peptides; D034741:RNA, Small Interfering; D018799:Intercellular Adhesion Molecule-1; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains