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Review
. 2024 Mar 30;25(7):3885.
doi: 10.3390/ijms25073885.

Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease-Is There a Link?

Aleksandra Stangret  1 , Karol Artur Sadowski  2 , Konrad Jabłoński  2 , Janusz Kochman  2 , Grzegorz Opolski  2 , Marcin Grabowski  2 , Mariusz Tomaniak  2
Affiliations
Review

Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease-Is There a Link?

Aleksandra Stangret et al. Int J Mol Sci. .

Abstract

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition.

Keywords: fractalkine/CX3CL1; non-obstructive coronary artery disease.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Known pathophysiological mechanisms underlying the development of NO-CAD.
Figure 2
Figure 2
Fractalkine role in the pathomechanisms of NO-CAD. Main leading causes of NO-CAD are coronary microvascular dysfunction (CMD), atherosclerotic changes within the coronary microcirculation and inflammation, which underlies these processes. In an inflamed endothelium there is an increased production of FKN/CX3CL1, which activates multiple intracellular signaling pathways via its receptor CX3CR1. FKN/CX3CL1 can bind to CX3CR1 expressed by monocytes, T lymphocytes and natural killer cells acting as a specific adhesion molecule, attracting these cells to the artery wall inflammatory process [80]. Monocyte adhesion to the endothelium is an initial stage of atherosclerosis. Recruited monocytes then transform into macrophages, engulf lipids, and exhibit morphological features of foam cells [100]. CX3CL1/CX3CR1 interactions regulate cell migration and proliferation through the Pl3K/Act signaling pathway. FKN/CX3CL1 induces vascular dysfunction by stimulating vascular ROS resulting in reduced NO bioavailability [110]. The decreased production of NO by impaired ECs increases collagen deposition, reduces angiogenesis and promotes the conversion of ECs into mesenchymal cells, leading to microvascular rarefaction [93]. Endothelial activation—defined by endothelial expression of VCAM-1, ICAM-1, P-selectin, E-selectin—is mainly due to activation of the NF-κB signaling cascade. NFĸB controls expression of FKN/CX3CL1 [112]. NFĸB can be activated through classical complex (IKKα/β/γ) and alternative pathways (NIK-mediated activation of IKKα). In the classical pathway, NFĸB dimers RelA/p50 are released from NFĸB inhibitors (IĸB). The non-classical pathway is activated by factors of TNF receptor (TNFR) superfamily members (TNFRSF). Direct activation of NFĸB-inducing kinase (NIK) phosphorylates an IKKα, which in turn leads to the liberation of the RelB/p52 complex [116]. In hypoxia, FKN/CX3CL1, which causes the adhesion of CX3CR1 expressing immune cells to ECs, leads to EC dysfunction and the initiation of a perivascular inflammatory response. Hypoxia and TNF-α increase hypoxia-inducible factor-1α (HIF-1α) expression via activation of the NFĸB classical pathway [117]. The figure was created in BioRender.com, accessed on 27 March 2024.
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