Background/Purpose:

Patients with chronic inflammatory diseases (CID) have higher risk of developing cardiovascular disease which may be in part due to increased systemic inflammatory burden. In atherosclerosis, extensive neovascularization is associated with plaque instability and an increased chance for myocardial infarction (MI). We have established that the non-canonical NF-κB pathway, with its central regulator NF-κB inducing kinase (NIK), in endothelial cells (EC) contributes to pathological angiogenesis in synovial tissue of patients with various forms of arthritis, including rheumatoid arthritis (RA). Thus, we hypothesized that NIK⁺EC may also contribute to neovascularization in atherosclerotic lesions.

Objective:

Evaluate expression of NIK in microvessels in atherosclerotic lesions from patients with and without CID and determine if it is associated with inflammatory cell influx, systemic inflammation or involvement of coronary arteries in MI.

Methods:

We obtained atherosclerotic coronary arteries from 11 individuals with CID (5 RA, 4 psoriasis, 2 inflammatory bowel disease) along with 11 matched controls without CID, all of whom died of fatal MI. Coronary arteries were immunohistochemically stained with antibodies against NIK, CD31/34 (EC), myeloperoxidase (neutrophils), CD45 (lymphocytes), CD68 (macrophages) and tryptase (mast cells). NIK positive vessel density (VD) (NIK⁺ vessels/mm2) and immune cell density (ICD cells/mm2) were calculated for right coronary artery (RCA) (internal control; remote area) and left anterior descending artery either implicated in MI (LAD+) or not (LAD-). Differences in NIK⁺ vessel density and cell densities in CID and controls, and between LAD+, LAD- and RCA, were analyzed using non-parametric Spearman’s Rank correlation or non-parametric Mann-Whitney U test.

Results:

NIK⁺ EC were present in atherosclerotic lesions of all coronary arteries. NIK⁺VD significantly correlated with ICD of all characterized immune cells: leukocytes (r=0.5227; p<0.0001), macrophages (r=0.3397, p<0.0001), mast cells (r=0.4205, p<0.0001) and neutrophils (r=0.2129, p=0.0016). No significant differences were found in NIK⁺VD in CID patients versus healthy, however, influx of leukocytes and macrophages per NIK⁺ microvessel was significantly higher in CID lesions. An increase in NIK⁺microvessels was also noted in LAD+ as compared to LAD- tissues (p=0.0139) in both healthy and CID patients.

Conclusion:

NIK⁺ microvessels are present in high numbers in atherosclerotic lesions  and are strongly associated with the influx of inflammatory cells. Systemic inflammation is not a prerequisite for activation of this pathway in EC in atherosclerotic lesions, but our findings suggest that non-canonical NF-κB signaling is more pronounced in patients with CID resulting in the attraction of more immune cells that may further enhance progression of atherosclerotic lesions. Since activation of the non-canonical NF-κB pathway in EC induces angiogenesis and NIK⁺ vessels are increased in coronary arteries associated with MI, non-canonical NF-κB signaling in EC may drive neovascularization and plaque instability, thus increasing the chance of developing a (fatal) MI.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/active-non-canonical-nf-kappab-signaling-in-microvessels-of-atherosclerotic-lesions-in-coronary-arteries-is-associated-with-inflammatory-cell-infiltration-and-myocardial-infarction/