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

• DOI: 10.1038/srep25636
• Publication Date: 2016-05-12T10:32:15Z
• Authors: Jihwa Chung; Hyunbo Shim; Kwanchang Kim; Duhwan Lee; Won Jong Kim; Dong Hoon Kang; Sang Won Kang; Hanjoong Jo; Kihwan Kwon
• Keywords: EXPRESSION; SELECTION; Male; 0301 basic medicine; Gene Expression; PHAGE; NONMUSCLE MYOSIN-II; Article; MECHANISMS; 03 medical and health sciences; INFLAMMATION; Animals; Humans; Amino Acid Sequence; RNA, Small Interfering; Cells, Cultured; SHEAR-STRESS; Myosin Heavy Chains; Nonmuscle Myosin Type IIA; MECHANOTRANSDUCTION; Endothelial Cells; Atherosclerosis; Intercellular Adhesion Molecule-1; Mice, Inbred C57BL; ATHEROSCLEROSIS; CELLS; Endothelium, Vascular; Peptides; Protein Binding

Abstract Atherosclerosis occurs preferentially in arterial regions exposed to disturbed blood flow. Targeting these pro-atherogenic is a potential anti-atherogenic therapeutic approach, but it has been extremely challenging. Here, using vivo phage display approach and the partial carotid ligation model of flow-induced atherosclerosis mouse, we identified novel peptides that specifically bind endothelial cells (ECs) flow condition regions. Two peptides, CLIRRTSIC CPRRSHPIC, selectively bound ECs not only partially ligated carotids also lesser curvature branching point aortic arch mice as well human pulmonary artery branches. Peptides were conjugated branched polyethylenimine-polyethylene glycol polymer generate polyplexes carrying siRNA targeting intercellular adhesion molecule-1 (siICAM-1). In mouse model, si-ICAM-1 endothelium regions, reducing ICAM-1 expression. Mass spectrometry analysis revealed non-muscle myosin heavy chain II A (NMHC IIA) protein targeted by peptide. Further studies showed shear stress regulates NMHC IIA expression localization ECs. The peptide could be used for delivery therapeutics such siRNAs endothelium.