Noncanonical NF-κB signaling in microvessels of atherosclerotic lesions is associated with inflammation, atheromatous plaque morphology and myocardial infarction

Chrissta X. Maracle, Rabia Agca, Boy Helder, John A.L. Meeuwsen, Hans W.M. Niessen, Erik A.L. Biessen, Menno P.J. de Winther, Saskia C.A. de Jager, Mike T. Nurmohamed, Sander W. Tas

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background and aims: Neovascularization is associated with atherosclerotic plaque instability and increased chance of myocardial infarction (MI). Patients with chronic inflammatory diseases (CID) have increased risk of atherosclerosis, and evidence demonstrates that NF-κB inducing kinase (NIK)-mediated noncanonical NF-κB signaling in endothelial cells (EC) is linked to inflammation and angiogenesis. Here, we hypothesized NIK may also be activated in EC of atherosclerotic lesion microvessels. Methods: Using cohorts of atherosclerotic lesions from coronary and carotid arteries, we quantified NIK expression in plaque microvessels and compared it to pathological markers, including inflammatory cell content, plaque characteristics and MI. Differences in gene transcripts were evaluated between stable and ruptured lesions. Results: NIK+EC were present in both coronary and carotid lesions. In CID patients, plaques with stenosis >40% had an increased number of NIK+EC and higher content of immune cells (p <.05) as compared to controls. Immune cells per NIK+EC were also greater in CID patients (p <.05), with pronounced differences as stenosis increased. In unstable lesions, NIK+EC were elevated as were EC expressing CXCL12 (p <.05). NIK+EC were increased in lesions with lipid content >40% (p <.05) and more abundant in coronary artery lesions implicated in MI (p <.05). These vessels also associated with atheromatous rather than fibrous plaque morphology (p <.05). Transcriptomic profiling demonstrated components of noncanonical NF-κB pathway were also upregulated in ruptured plaques (p <.05). Conclusions: NIK+EC associate with chronic inflammation in advanced lesions and are linked to markers of local inflammation, lipid content, unstable plaque phenotype and development of MI. Therefore, targeting noncanonical NF-κB signaling may hold therapeutic potential for patients with atherosclerosis and cardiovascular disease.

Original languageEnglish
Pages (from-to)33-41
Number of pages9
JournalAtherosclerosis
Volume270
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

Maracle, Chrissta X. ; Agca, Rabia ; Helder, Boy ; Meeuwsen, John A.L. ; Niessen, Hans W.M. ; Biessen, Erik A.L. ; de Winther, Menno P.J. ; de Jager, Saskia C.A. ; Nurmohamed, Mike T. ; Tas, Sander W. / Noncanonical NF-κB signaling in microvessels of atherosclerotic lesions is associated with inflammation, atheromatous plaque morphology and myocardial infarction. In: Atherosclerosis. 2018 ; Vol. 270. pp. 33-41.
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title = "Noncanonical NF-κB signaling in microvessels of atherosclerotic lesions is associated with inflammation, atheromatous plaque morphology and myocardial infarction",
abstract = "Background and aims: Neovascularization is associated with atherosclerotic plaque instability and increased chance of myocardial infarction (MI). Patients with chronic inflammatory diseases (CID) have increased risk of atherosclerosis, and evidence demonstrates that NF-κB inducing kinase (NIK)-mediated noncanonical NF-κB signaling in endothelial cells (EC) is linked to inflammation and angiogenesis. Here, we hypothesized NIK may also be activated in EC of atherosclerotic lesion microvessels. Methods: Using cohorts of atherosclerotic lesions from coronary and carotid arteries, we quantified NIK expression in plaque microvessels and compared it to pathological markers, including inflammatory cell content, plaque characteristics and MI. Differences in gene transcripts were evaluated between stable and ruptured lesions. Results: NIK+EC were present in both coronary and carotid lesions. In CID patients, plaques with stenosis >40{\%} had an increased number of NIK+EC and higher content of immune cells (p <.05) as compared to controls. Immune cells per NIK+EC were also greater in CID patients (p <.05), with pronounced differences as stenosis increased. In unstable lesions, NIK+EC were elevated as were EC expressing CXCL12 (p <.05). NIK+EC were increased in lesions with lipid content >40{\%} (p <.05) and more abundant in coronary artery lesions implicated in MI (p <.05). These vessels also associated with atheromatous rather than fibrous plaque morphology (p <.05). Transcriptomic profiling demonstrated components of noncanonical NF-κB pathway were also upregulated in ruptured plaques (p <.05). Conclusions: NIK+EC associate with chronic inflammation in advanced lesions and are linked to markers of local inflammation, lipid content, unstable plaque phenotype and development of MI. Therefore, targeting noncanonical NF-κB signaling may hold therapeutic potential for patients with atherosclerosis and cardiovascular disease.",
keywords = "Angiogenesis, Atherosclerosis, Cell signaling, Inflammation, Nuclear factor kappaB",
author = "Maracle, {Chrissta X.} and Rabia Agca and Boy Helder and Meeuwsen, {John A.L.} and Niessen, {Hans W.M.} and Biessen, {Erik A.L.} and {de Winther}, {Menno P.J.} and {de Jager}, {Saskia C.A.} and Nurmohamed, {Mike T.} and Tas, {Sander W.}",
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language = "English",
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Noncanonical NF-κB signaling in microvessels of atherosclerotic lesions is associated with inflammation, atheromatous plaque morphology and myocardial infarction. / Maracle, Chrissta X.; Agca, Rabia; Helder, Boy; Meeuwsen, John A.L.; Niessen, Hans W.M.; Biessen, Erik A.L.; de Winther, Menno P.J.; de Jager, Saskia C.A.; Nurmohamed, Mike T.; Tas, Sander W.

In: Atherosclerosis, Vol. 270, 01.03.2018, p. 33-41.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Noncanonical NF-κB signaling in microvessels of atherosclerotic lesions is associated with inflammation, atheromatous plaque morphology and myocardial infarction

AU - Maracle, Chrissta X.

AU - Agca, Rabia

AU - Helder, Boy

AU - Meeuwsen, John A.L.

AU - Niessen, Hans W.M.

AU - Biessen, Erik A.L.

AU - de Winther, Menno P.J.

AU - de Jager, Saskia C.A.

AU - Nurmohamed, Mike T.

AU - Tas, Sander W.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Background and aims: Neovascularization is associated with atherosclerotic plaque instability and increased chance of myocardial infarction (MI). Patients with chronic inflammatory diseases (CID) have increased risk of atherosclerosis, and evidence demonstrates that NF-κB inducing kinase (NIK)-mediated noncanonical NF-κB signaling in endothelial cells (EC) is linked to inflammation and angiogenesis. Here, we hypothesized NIK may also be activated in EC of atherosclerotic lesion microvessels. Methods: Using cohorts of atherosclerotic lesions from coronary and carotid arteries, we quantified NIK expression in plaque microvessels and compared it to pathological markers, including inflammatory cell content, plaque characteristics and MI. Differences in gene transcripts were evaluated between stable and ruptured lesions. Results: NIK+EC were present in both coronary and carotid lesions. In CID patients, plaques with stenosis >40% had an increased number of NIK+EC and higher content of immune cells (p <.05) as compared to controls. Immune cells per NIK+EC were also greater in CID patients (p <.05), with pronounced differences as stenosis increased. In unstable lesions, NIK+EC were elevated as were EC expressing CXCL12 (p <.05). NIK+EC were increased in lesions with lipid content >40% (p <.05) and more abundant in coronary artery lesions implicated in MI (p <.05). These vessels also associated with atheromatous rather than fibrous plaque morphology (p <.05). Transcriptomic profiling demonstrated components of noncanonical NF-κB pathway were also upregulated in ruptured plaques (p <.05). Conclusions: NIK+EC associate with chronic inflammation in advanced lesions and are linked to markers of local inflammation, lipid content, unstable plaque phenotype and development of MI. Therefore, targeting noncanonical NF-κB signaling may hold therapeutic potential for patients with atherosclerosis and cardiovascular disease.

AB - Background and aims: Neovascularization is associated with atherosclerotic plaque instability and increased chance of myocardial infarction (MI). Patients with chronic inflammatory diseases (CID) have increased risk of atherosclerosis, and evidence demonstrates that NF-κB inducing kinase (NIK)-mediated noncanonical NF-κB signaling in endothelial cells (EC) is linked to inflammation and angiogenesis. Here, we hypothesized NIK may also be activated in EC of atherosclerotic lesion microvessels. Methods: Using cohorts of atherosclerotic lesions from coronary and carotid arteries, we quantified NIK expression in plaque microvessels and compared it to pathological markers, including inflammatory cell content, plaque characteristics and MI. Differences in gene transcripts were evaluated between stable and ruptured lesions. Results: NIK+EC were present in both coronary and carotid lesions. In CID patients, plaques with stenosis >40% had an increased number of NIK+EC and higher content of immune cells (p <.05) as compared to controls. Immune cells per NIK+EC were also greater in CID patients (p <.05), with pronounced differences as stenosis increased. In unstable lesions, NIK+EC were elevated as were EC expressing CXCL12 (p <.05). NIK+EC were increased in lesions with lipid content >40% (p <.05) and more abundant in coronary artery lesions implicated in MI (p <.05). These vessels also associated with atheromatous rather than fibrous plaque morphology (p <.05). Transcriptomic profiling demonstrated components of noncanonical NF-κB pathway were also upregulated in ruptured plaques (p <.05). Conclusions: NIK+EC associate with chronic inflammation in advanced lesions and are linked to markers of local inflammation, lipid content, unstable plaque phenotype and development of MI. Therefore, targeting noncanonical NF-κB signaling may hold therapeutic potential for patients with atherosclerosis and cardiovascular disease.

KW - Angiogenesis

KW - Atherosclerosis

KW - Cell signaling

KW - Inflammation

KW - Nuclear factor kappaB

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U2 - 10.1016/j.atherosclerosis.2018.01.032

DO - 10.1016/j.atherosclerosis.2018.01.032

M3 - Article

VL - 270

SP - 33

EP - 41

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

ER -