No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
AhR, IRF5, and HO-1 Expression in Evaluating Carotid Atherosclerotic Plaque Vulnerability: A Pilot Observational Study
ResearchGate has not been able to resolve any citations for this publication.
Aims
Inflammation is a key factor in atherosclerosis. The transcription factor interferon regulatory factor-5 (IRF5) drives macrophages towards a pro-inflammatory state. We investigated the role of IRF5 in human atherosclerosis and plaque stability.
Methods and results
Bulk RNA sequencing from the Carotid Plaque Imaging Project biobank were used to mine associations between major macrophage associated genes and transcription factors and human symptomatic carotid disease. Immunohistochemistry, proximity extension assays, and Helios cytometry by time of flight (CyTOF) were used for validation. The effect of IRF5 deficiency on carotid plaque phenotype and rupture in ApoE−/− mice was studied in an inducible model of plaque rupture. Interferon regulatory factor-5 and ITGAX/CD11c were identified as the macrophage associated genes with the strongest associations with symptomatic carotid disease. Expression of IRF5 and ITGAX/CD11c correlated with the vulnerability index, pro-inflammatory plaque cytokine levels, necrotic core area, and with each other. Macrophages were the predominant CD11c-expressing immune cells in the plaque by CyTOF and immunohistochemistry. Interferon regulatory factor-5 immunopositive areas were predominantly found within CD11c+ areas with a predilection for the shoulder region, the area of the human plaque most prone to rupture. Accordingly, an inducible plaque rupture model of ApoE−/−Irf5−/− mice had significantly lower frequencies of carotid plaque ruptures, smaller necrotic cores, and less CD11c+ macrophages than their IRF5-competent counterparts.
Conclusion
Using complementary evidence from data from human carotid endarterectomies and a murine model of inducible rupture of carotid artery plaque in IRF5-deficient mice, we demonstrate a mechanistic link between the pro-inflammatory transcription factor IRF5, macrophage phenotype, plaque inflammation, and its vulnerability to rupture.
As a chronic inflammatory disease with autoimmune components, atherosclerosis is the major cause of cardiovascular morbidity and mortality. Recent studies have revealed that the development of atherosclerosis is strongly linked to the functional activities of aryl hydrocarbon receptor (AHR), a chemical sensor that is also important for the development, maintenance, and function of a variety of immune cells. In this review, we focus on the impact of AHR signaling on the different cell types that are closely related to the atherogenesis, including T cells, B cells, dendritic cells, macrophages, foam cells, and hematopoietic stem cells in the arterial walls, and summarize the latest development on the interplay between this environmental sensor and immune cells in the context of atherosclerosis. Hopefully, elucidation of the role of AHR in atherosclerosis will facilitate the understanding of case variation in disease prevalence and may aid in the development of novel therapies.
Background and Purpose—
Heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to generate carbon monoxide, biliverdin, and iron. Because these products have antiatherogenic properties, HO-1 may play a protective role against atherosclerosis. However, plasma HO-1 levels in patients with carotid atherosclerosis have not been reported.
Methods—
We investigated plasma HO-1 levels by ELISA in 136 subjects (age, 66±9 years) undergoing carotid ultrasonography.
Results—
Of the 136 study subjects, carotid plaque was found in 61 subjects (45%). Compared with 75 subjects without plaque, 61 with plaque were older and predominantly male ( P <0.05). Plasma HO-1 levels were higher in subjects with plaque than in those without plaque (median, 0.56 versus 0.44 ng/mL; P <0.05). The percentage of subjects with HO-1 level >0.50 ng/mL was higher in subjects with plaque than without plaque (66% versus 44%; P <0.025). In multivariate analysis, HO-1 level was a significant factor for carotid plaque independent of atherosclerotic risk factors. Odds ratio for plaque was 2.33 (95% CI, 1.15–4.75) for HO-1 level >0.50 ng/mL.
Conclusions—
Plasma HO-1 levels were high in subjects with carotid plaques, probably reflecting a protective response against carotid atherosclerosis.
The European Carotid Surgery Trial (ECST) is an ongoing randomised trial of immediate carotid endarterectomy vs non-surgery in symptomatic patients with recent and mild carotid territory ischaemic events. So far it is become clear that the risk of the operation is--in general--worth taking in patients with "severe" stenosis (> 70% of the proximal internal carotid artery diameter) but not in patients with "mild" stenosis (0-29%). The balance of risk vs benefit in patients with "moderate" stenosis (30-69%) is still unclear und recruitment of such patients continues. All patients are still being followed up to assess the durability of any benefit of surgery and to develop prognostic models to predict the risk of ipsilateral ischemic stroke in the no-surgery patients. Also, further studies are being done to investigate the best method of measuring the amount of disease at the carotid bifurcation.