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: Gabrielle Fredman, Nazila Kamaly, Stefano Spolitu, Jaclyn Milton, Devram Ghorpade, Raymond Chiasson, George Kuriakose, Mauro Perretti, Omid Farokzhad, Ira Tabas
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 275 Pg. 275ra20 (Feb 18 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 25695999 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Annexin A1
• Collagen Type IV
• Peptides
• Receptors, LDL
• annexin A1 peptide (2-26)

Topics

• Animals
• Annexin A1 (pharmacology)
• Atherosclerosis (complications, metabolism, prevention & control)
• Collagen Type IV (metabolism)
• Hypercholesterolemia (complications, metabolism)
• Mice
• Mice, Knockout
• Nanoparticles
• Oxidative Stress
• Peptides (pharmacology)
• Receptors, LDL (genetics, physiology)