title: Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice.
abstract: Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2-26 (Ac2-26). Collagen IV (Col IV)-targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr(-/-) mice. When administered to mice with preexisting lesions, Col IV-Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.
authors.affiliation: Departments of Medicine, Pathology & Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nazila
authors.initials: N
authors.lastname: Kamaly
authors.affiliation: Departments of Medicine, Pathology & Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Spolitu
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Milton
authors.affiliation: Departments of Medicine, Pathology & Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA.
authors.forename: Devram
authors.initials: D
authors.lastname: Ghorpade
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Chiasson
authors.affiliation: Departments of Medicine, Pathology & Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kuriakose
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Farokzhad
authors.affiliation: Departments of Medicine, Pathology & Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000494:pharmacology*; D050197:Atherosclerosis / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D024141:Collagen Type IV / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053758:Nanoparticles; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology*; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology
chemical_list: D017305:Annexin A1; D024141:Collagen Type IV; D010455:Peptides; D011973:Receptors, LDL; C096153:annexin A1 peptide (2-26)