Discovery of novel peptides targeting pro-atherogenic endothelium in disturbed flow regions -Targeted siRNA delivery to pro-atherogenic endothelium in vivo

• Type of Material: Article
• Authors: Jihwa Chung, Ewha Womans University; Hyunbo Shim, Ewha Womans University; Kwanchang Kim, Ewha Womans University; Duhwan Lee, Pohang Univ Sci & Technol POSTECH; Won Jong Kim, Pohang Univ Sci & Technol POSTECH; Dong Hoon Kang, Ewha Womans University; Sang Won Kang, Ewha Womans University; Hanjoong Jo, Emory University; Kihwan Kwon, Ewha Womans University
• Language: English
• Date: 2016-05-12
• Publisher: Nature Publishing Group: Open Access Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2016, Macmillan Publishers Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/srep25636
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 6
• Start Page: 25636
• End Page: 25636
• Grant/Funding Information: This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MEST) (No. 2011-0019695) and Ewha Global Top 5 Grant 2013 of Ewha Womans University.
• Keywords: Science & Technology - Other Topics; EXPRESSION; Multidisciplinary Sciences; FLUID SHEAR-STRESS; INFLAMMATION; NONMUSCLE MYOSIN-II; CELLS; MECHANOTRANSDUCTION; ATHEROSCLEROSIS; MICE; MECHANISMS; PHAGE-DISPLAY; Science & Technology
• Research Categories: Health Sciences, General; Health Sciences, Medicine and Surgery; Engineering, Biomedical

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.