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.

Annexins – insights from knockout mice

“…In cell models, all three members of the human FPR family showed activation by N-terminal AnxA1-derived peptides (Ernst et al, 2004). Then, after initial in vivo studies in mouse strains lacking the structurally related FPR1 ( Perretti and D'Acquisto, 2009), analysis of the FPR2 -/-mice (Dufton et al, 2010;Dalli et al, 2013;Buss et al, 2015;Drechsler et al, 2015;Fredman et al, 2015;McArthur et al, 2015;Smith et al, 2015) provided more conclusive information that AnxA1 mediated innate immune reactions via FPR2 (also known as lipoxin A4 receptor or ALX) ( Table 2). How the interaction of AnxA1 with FPR2 translates into the multiple and diverse molecular events that drive immune response is not fully understood, but activation of mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinases 1/2 (Erk1/2) and p38MAPK, Akt, c-Jun N-terminal kinase, increase of intracellular Ca 2+ levels appear to be involved.…”

“…Along these lines, Fredman and coworkers packaged Ac2-26 onto nanoparticles that target collagen type IV, which is highly enriched in atherosclerotic plaque, thereby reducing mistargeting and systemic side effects. Advanced atheroslerotic lesions from mice receiving these nanoparticles showed reduced lesion instability in an FPR2-dependent manner (Fredman et al, 2015). Nevertheless, the mechanisms enabling AnxA1 to reduce the risk of lesion rupture are still not fully understood.…”

Erratum: Inflammatory processes in cardiovascular disease: a route to targeted therapies

“…The same tools can also be used to monitor response to treatment 158 (including toxicity 159 ). Some preclinical examples include studies in which either IL-13 (which polarizes macrophages to the M2 state) or a ligand of resolving receptors on macrophages were effective in retarding the progression of atherosclerosis 160,161 .…”

MRI Investigation of New Approach to Improve the Recovery of Myocardial Ischemia Reperfusion Injury by Treatment with Intralipid<sup>®</sup>

“…Macrophages/monocytes (MØs) are the most common and crucial cardiac inflammatory cells in myocardial IRI [4] [6] [7], atherosclerosis [8] [9], MI [10], myocarditis [11], and cardiac transplantation [12]- [17]. Recently, it has been reported that negatively charged microparticles, synthesized from carboxylated polystyrene or poly(lactic-co-glycolic acid), can immune-modify MØs, reduce the infiltration of MØs to the sites of inflammation, and, thus, reduce the disease symptoms, e.g., cardiac IRI, kidney IRI, West Nile virus encephalitis, and inflammatory bowel disease [4] [18].…”