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Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.

ABSTRACT: Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that, in contrast to apoptosis, induces a proinflammatory state. We show herein that necroptotic cell death is activated in human advanced atherosclerotic plaques and can be targeted in experimental atherosclerosis for both therapeutic and diagnostic interventions. In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased, and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying necroptosis showed that atherogenic forms of low-density lipoprotein increase RIP3 and MLKL transcription and phosphorylation-two critical steps in the execution of necroptosis. Using a radiotracer developed with the necroptosis inhibitor necrostatin-1 (Nec-1), we show that (123)I-Nec-1 localizes specifically to atherosclerotic plaques in Apoe (-/-) mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe (-/-) mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Collectively, our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis.

SUBMITTER: Karunakaran D

PROVIDER: S-EPMC4985228 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.

Karunakaran Denuja D Geoffrion Michele M Wei Lihui L Gan Wei W Richards Laura L Shangari Prakriti P DeKemp Ella M EM Beanlands Rachelle A RA Perisic Ljubica L Maegdefessel Lars L Hedin Ulf U Sad Subash S Guo Liang L Guo Liang L Kolodgie Frank D FD Virmani Renu R Ruddy Terrence T Rayner Katey J KJ

Science advances 20160722 7

Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of program ...[more]

PMID: 27532042

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Project description:Atherosclerosis (AS) is a chronic inflammatory disease, which has a complex interplay between altered immune metabolism and oxidative stress. Therefore, we aimed to determine the oxidative stress and immune-related biomarkers in AS. Differential gene expression analyses are based on the GSE100927 dataset in the Gene Expression Omnibus (GEO), and 389 oxidative stress (OS) genes are identified based on gene set enrichment analysis (GSEA). We identified 74 differentially expressed genes related to oxidative stress (DEOSGs). "CIBERSORT" and "WGCNA" R Packages were used to compare the differences in immune infiltration levels between AS and control samples. The DEOSGs (N = 74) were intersected with the key module's genes of WGCNA (N = 972), and 27 differentially expressed immune-related oxidative stress genes (DEIOSGs) were obtained. To identify the pivotal genes, a protein-protein interaction (PPI) network was constructed using the STRING database and the Cytoscape software. MMP9, ALOX5, NCF2, NCF, and NCF4 were identified as diagnostic markers of AS, and we validated them in the GSE57691 dataset. The expression levels of the five diagnostic genes were significantly highly expressed in the AS group. Correlation analysis and single-cell analysis revealed that five diagnostic genes were mainly correlated with macrophages M1. We, respectively, intersected differentially expressed genes (DEGs) with ferroptosis gene set, necroptosis gene set, and pyroptosis gene set. The findings suggested that ALOX5 and NCF2 were differentially expressed genes of ferroptosis. High expression of five hub genes in RAW264.7 macrophages were confirmed by PCR. High ALOX5 and NCF2 expression levels in plaque tissues were confirmed by immunohistochemistry (IHC) and western blotting. Our study identified that MMP9, ALOX5, NCF2, NCF1, and NCF4 were diagnostic genes of AS and associated with oxidative stress. ALOX5 and NCF2 may be involved in the formation of the necrotic core in AS by regulating macrophage ferroptosis.

Dataset Information

Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.

Publications

Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.

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