title: Plaque-penetrating peptide inhibits development of hypoxic atherosclerotic plaque.
abstract: Atherosclerosis treatments are generally aimed at altering systemic lipid metabolism such that atherogenesis, the formation of plaque, is curtailed. The plaques themselves offer some potential therapeutic targets. For example, selective depletion of macrophages, which play a key role in atherogenesis, inhibits plaque formation. However, it has not been possible to take advantage of these targets because the drugs that have been tested have not been sufficiently selective. We have developed a peptide, LyP-1, which specifically targets atherosclerotic plaques, penetrates into plaque interior, and accumulates in plaque macrophages. In tumors, LyP-1 can cause apoptosis in cells that take up the peptide. Here we show, using three different atherosclerosis models in ApoE null mice that prolonged systemic treatment with LyP-1 triggers apoptosis of plaque macrophages and reduces plaque in advanced hypoxic plaques, and that it does so without increasing necrotic core of plaques or causing detectable side effects. We also show that LyP-1 recognizes human plaque. These findings suggest that LyP-1 could serve as a lead compound for the development of a new class of anti-atherosclerosis drugs.
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.affiliation: Center for Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-961, USA; Harry Perkins Institute of Medical Research, The University of Western Australia, QEII Medical Centre, 6 Verdun Street, Nedlands, WA 6009, Australia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Hamzah
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA.
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Kotamraju
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Pang
authors.affiliation: Department of Vascular and Endovascular Surgery, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; Curtin University, Kent St, Bentley, WA 6102, Australia.
authors.forename: Shirley
authors.initials: S
authors.lastname: Jansen
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA; Center for Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-961, USA. Electronic address: ruoslahti@SBPdiscovery.org.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; C533969:LyP-1 peptide; D010456:Peptides, Cyclic
keywords: Arterial occlusion; Endothelium; Plaque-associated macrophages; Tumor-homing peptide; p32/p33/gC1qR/HABP