Research ArticlesCardiovascular

Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice

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Science Translational Medicine  18 Feb 2015:
Vol. 7, Issue 275, pp. 275ra20
DOI: 10.1126/scitranslmed.aaa1065

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Inflammation resolution: A solution for advanced atherosclerosis

In atherosclerosis, fatty plaques build up in the arteries. It is therefore common that people with cardiovascular disease at risk for atherosclerosis will take statins, or lipid-lowering drugs. However, a complementary approach may be to resolve the ongoing, chronic inflammation in atherosclerosis. Such a proresolving tactic was adopted by Fredman et al. The authors encapsulated a small fragment of annexin A1—a protein that promotes the resolution of inflammation—in a polymeric nanoparticle, and decorated the nanoparticle with a collagen IV–binding peptide, to target the therapeutic package to advanced atherosclerotic plaques. The Ac2-26 nanoparticles accumulated at vessel lesions in a mouse model of advanced atherosclerosis. Once in place, the particles slowly released Ac2-26, which bound to immune cells, reducing oxidative stress, promoting collagen buildup, and increasing the anti-inflammatory cytokine interleukin-10—in sum, working to resolve inflammation and stabilize the plaque. This new proresolving nanomedicine approach will need to be tested in larger vessels and in animal models more similar to human atherosclerosis. But this targeted therapy is a first of its kind, paving the way for a new type of therapy to prevent heart disease.

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.

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