Associations between circulating proteins and corresponding genes expressed in coronary thrombi in patients with acute myocardial infarction

Helseth, Ragnhild; Weiss, Thomas W.; Opstad, Trine Baur; Siegbahn, Agneta; Solheim, Svein; Freynhofer, Matthias K.; Huber, Kurt; Arnesen, Harald; Seljeflot, Seljeflot

doi:10.1016/j.thromres.2015.10.005

Cited by 6 publications

(5 citation statements)

References 41 publications

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“…32, 33 However, other studies showed no link between circulating MPO protein and cardiovascular risk. 34, 35 Most studies demonstrating a correlation between circulating MPO protein and future events used enriched populations who had already experienced plaque destabilization. Like these studies, we observed plasma concentration of MPO protein to be elevated in patients with ruptured compared with stable plaques ( Figure S8B ).…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase activity predicts atherosclerotic plaque disruption and atherothrombosis

Nadel,

Wang,

Saha

et al. 2023

Preprint

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BackgroundUnstable atherosclerotic plaque is characterized by increased myeloperoxidase (MPO) activity. As unstable plaque is vulnerable to disruption and ensuing thrombosis, we examined whether plaque MPO activity predicts atherothrombosis in a pre-clinical model and correlates with ruptured human atheroma.MethodsTo assess if plaque MPO activity predicts atherothrombosis, rabbits were subjected to aortic endothelial denudation, cholesterol feeding,in vivomagnetic resonance imaging (MRI) of MPO activity using MPO-Gd (gadolinium), followed by pharmacological triggering of atherothrombosis, histology, and MPO activity determined by liquid chromatography tandem mass spectrometry (LC-MSMS) by quantifying the MPO-specific product of hydroethidine, 2-chloroethidium. To correlate plaque MPO activity to ruptured human atheroma,ex vivodetermination of MPO activity by MPO-Gd retention in carotid endarterectomy (CEA) specimens was correlated within vivoMRI plaque phenotyping in patients, histology, and MPO activity determined by LC-MSMS.ResultsIn rabbits, pre-triggerin vivoMPO activity, validated by LC-MSMS and histology, was higher in thrombosis-prone than thrombosis-resistant plaques and lesion-free segments (R1 relaxation rate = 2.2 ± 0.4 versus 1.6 ± 0.2 and 1.5 ± 0.2 s-1, respectively, p<0.0001), and it predicted atherothrombosis. In CEA specimens, MPO-Gd retention was greater in histologic and MRI-graded American Heart Association (AHA) type VI than types III, IV and V plaques (ΔR1 relaxation rate from baseline = 48 ± 6 versus 16 ± 7, 17 ± 8 and 23 ± 8%, respectively, p<0.0001). This association was confirmed by comparing AHA grade to MPO activity determined by LC-MSMS (277 ± 338 versus 7 ± 6, 11 ± 12 and 42 ± 39 pmol 2-chloroethidium/mg protein for type VI versus type III-V plaques, respectively, p=0.0008).ConclusionsMPO activity is elevated in thrombosis-prone rabbit and ruptured human atheroma. Non-invasive molecular imaging of MPO activity predicts atherothrombosis, highlighting the potential of arterial MPO activity to detect vulnerable, destabilized atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Myeloperoxidase activity predicts atherosclerotic plaque disruption and atherothrombosis

Nadel,

Wang,

Saha

et al. 2023

Preprint

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“…A study was performed to identify the different circulating proteins present in the event of an acute coronary syndrome, with the majority being STEMI patients. Helseth et al identified a significant inverse relationship between total ischaemic time with soluble FKN (sFKN) levels where the cut-off was more or less than 4 h [51]. However, this study was not consistent in terms of timing of venepuncture as it was performed between 6 and 24 h of the PCI procedure with a median time of 18 h. Hence, an important study was subsequently performed by Njerve et al, which managed to demonstrate that in comparison to patients with stable angina, those with an acute MI were found to have statistically significant higher levels of FKN up to 12 h post procedure [52].…”

Section: Significance Of Fractalkine and Its Receptor In Myocardial I...mentioning

confidence: 99%

Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging Target in Coronary Artery Disease

Loh,

Ekinci,

Spray

et al. 2023

JCM

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Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CX3CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX3CR1. We have shown previously that the fractalkine receptor CX3CR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CX3CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX3CR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.

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“…The CD40:CD40L two-way immune checkpoint promotes atherosclerosis and inhibits tumor progress and has been used as a cancer immunotherapy target [60–62]. sCD40L is significantly elevated in patients with cardiovascular disease (CVD) and CKD [15] and proposed as an independent predictor and biomarker for cardiovascular events after acute coronary syndrome and plaque vulnerability [63]. CD40:CD40L interactions stimulate the expression of inflammatory cytokines, adhesion molecules, chemokines, matrix degrading enzymes, and platelet tissue factor.…”

Section: Two-way Stimulatory Immune Checkpoint Induces Tissue and Sysmentioning

confidence: 99%

Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation

Dai

Saredy

et al. 2017

J Hematol Oncol

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Adaptive immunity is critical for disease progression and modulates T cell (TC) and antigen-presenting cell (APC) functions. Three signals were initially proposed for adaptive immune activation: signal 1 antigen recognition, signal 2 co-stimulation or co-inhibition, and signal 3 cytokine stimulation. In this article, we propose to term signal 2 as an immune checkpoint, which describes interactions of paired molecules leading to stimulation (stimulatory immune checkpoint) or inhibition (inhibitory immune checkpoint) of an immune response. We classify immune checkpoint into two categories: one-way immune checkpoint for forward signaling towards TC only, and two-way immune checkpoint for both forward and reverse signaling towards TC and APC, respectively. Recently, we and others provided evidence suggesting that metabolic risk factors (RF) activate innate and adaptive immunity, involving the induction of immune checkpoint molecules. We summarize these findings and suggest a novel theory, metabolism-associated danger signal (MADS) recognition, by which metabolic RF activate innate and adaptive immunity. We emphasize that MADS activates the reverse immune checkpoint which leads to APC inflammation in innate and adaptive immunity. Our recent evidence is shown that metabolic RF, such as uremic toxin or hyperhomocysteinemia, induced immune checkpoint molecule CD40 expression in monocytes (MC) and elevated serum soluble CD40 ligand (sCD40L) resulting in CD40+ MC differentiation. We propose that CD40+ MC is a novel pro-inflammatory MC subset and a reliable biomarker for chronic kidney disease severity. We summarize that CD40:CD40L immune checkpoint can induce TC and APC activation via forward stimulatory, reverse stimulatory, and TC contact-independent immune checkpoints. Finally, we modeled metabolic RF-induced two-way stimulatory immune checkpoint amplification and discussed potential signaling pathways including AP-1, NF-κB, NFAT, STAT, and DNA methylation and their contribution to systemic and tissue inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0504-1) contains supplementary material, which is available to authorized users.

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Associations between circulating proteins and corresponding genes expressed in coronary thrombi in patients with acute myocardial infarction

Cited by 6 publications

References 41 publications

Myeloperoxidase activity predicts atherosclerotic plaque disruption and atherothrombosis

Myeloperoxidase activity predicts atherosclerotic plaque disruption and atherothrombosis

Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging Target in Coronary Artery Disease

Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation

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