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Updated: Mar 17, 2026
The Rabbit Model of Accelerated Atherosclerosis: A Methodological Perspective of the Iliac Artery Balloon Injury
Published on: October 3, 2017
TREM-1 inhibition with LR12 attenuates in-stent neoatherosclerosis through modulating macrophage polarization in a
Mengting Jiang1, Yingqian Zhang2, Xiaohang Yuan2
1Senior Department of Cardiology, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
Background:
In-stent neoatherosclerosis (ISNA) contributes significantly to late stent thrombosis and in-stent restenosis. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a key amplifier of inflammation; however, its role in ISNA pathogenesis remains unexplored. In this study, we investigated the effects of pharmacologically inhibiting TREM-1 with a novel clinical agent LR12 (nangibotide) on ISNA development in an experimental model.
Methods:
A rabbit model of ISNA was established using high-fat diet (HFD)-fed male New Zealand rabbits (3-4 months old) undergoing aortic balloon angioplasty and implantation of a second-generation drug-eluting stent. A total of 40 rabbits were randomized to receive the TREM-1 inhibitor LR12 or saline post-stenting, with endpoints assessed at 1 and 3 months (n = 10). Optical coherence tomography (OCT) evaluated ISNA formation and stent healing. Serum biomarkers, histopathology, immunofluorescence, and in vitro macrophage polarization studies were performed.
Results:
OCT demonstrated LR12 markedly attenuated ISNA area (40.5% reduction at 1 month [1.25 ± 0.41 vs. 2.10 ± 0.68 mm2, P = 0.045]; 48.7% at 3 months [2.18 ± 0.49 vs. 4.25 ± 1.33 mm2, P = 0.005]) and neointimal thickness at 3 months (383.02 ± 59.54 vs. 555.63 ± 136.26 μm, P = 0.004) without impairing stent endothelialization. LR12 promoted a shift in macrophage polarization towards anti-inflammatory M2 type (decreased TNF-α/ARG-1 ratio, P < 0.05) and suppressed systematical and local pro-inflammatory cytokines (IL-6, IL-12; P < 0.05). Mechanistically, TREM-1 inhibition reduced ox-LDL-induced foam cell formation and modulated macrophage polarization via the JAK1-STAT1/STAT3 pathway in vitro.
Conclusions:
Pharmacological inhibition of TREM-1 using LR12 effectively suppresses ISNA development without compromising stent healing, probably by inhibiting pro-inflammatory M1 polarization and promoting anti-inflammatory M2 macrophage phenotypes through modulation of the JAK1-STAT1/STAT3 signaling pathway. These results motivate further trials evaluating LR12 as a promising therapeutic strategy targeting inflammation to prevent ISNA in patients.
