Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Abstract

Atherosclerosis is a progressive, multifactorial inflammatory, and dyslipidaemic disease, responsible for the majority of cardiovascular diseases globally. The chronic inflammation is the main driver of the initiation and progression of such disease, as a result of an imbalanced lipid metabolism and an ineffective immune response to attenuate the inflammatory component. The importance of inflammation resolution is being increasingly recognised in atherosclerosis and cardiovascular disease. It has a complex mechanism consisting of multiple stages, including restoring an effective removal of apoptotic bodies (efferocytosis) and their degradation (effero-metabolism), a macrophage phenotype switching towards resolving phenotypes, and the promotion of tissue healing and regeneration. The low-grade inflammation associated with atherosclerosis development is a driving force in disease exacerbation, and hence inflammation resolution is a key area of research. In this review, we explore the complex disease pathogenesis and its many contributing factors to gain a greater understanding of the disease and identify the current and potential therapeutic targets. First-line treatments and their efficacy will also be discussed in detail, to highlight the emerging field of resolution pharmacology. Despite the great efforts made by current gold-standard treatments, such as lipid-lowering and glucose-lowering drugs, they remain ineffective at tackling residual inflammatory risk and residual cholesterol risk. Resolution pharmacology represents a new era of atherosclerosis therapy, as endogenous ligands associated with inflammation resolution are exploited for their pharmacological benefits in a more potent and longer-acting manner. Novel FPR2-agonists, such as synthetic lipoxin analogues, provide an exciting new approach to enhance the pro-resolving response of the immune system and subsequently end the pro-inflammatory response to allow for an anti-inflammatory and pro-resolving environment for tissue healing, regeneration, and return to homeostasis.

Keywords: FPR2; cardiovascular disease; efferocytosis; glucose-lowering drugs; lipid-lowering drugs; resolution pharmacology; synthetic lipoxin mimetics.

FIGURE 1

Progression of Atherosclerosis. The development of atherosclerosis is a 5-step process from the initial development of the fatty streak into an atherosclerotic lesion, through to the development/rupturing of fibrofatty atheroma. During atheroma development, patients develop hypertension as the artery becomes narrowed or completely blocked, forcing the heart to pump harder to pass blood through. Elasticity of the vascular tissue allows some flexibility as the lumen narrows, and the mediators of this elasticity also promote the formation of the fibrotic cap on the plaque, providing stability. However, the subsequent rupturing of this plaque can lead to a myocardial infarction by blocking cardiac blood supply or may even cause plaque debris to travel to blood vessels, reaching distant organs (i.e., brain, kidneys, heart) and causing an infarction (heart or kidneys), or a stroke (brain). In this diagram, an example of coronary atherosclerosis development is depicted. Atherosclerosis can also form in the aortic arch, as well as in carotid and femoral arteries (Figure made with BioRender.com).

FIGURE 2

Plaque formation and Rupture. As the plaque develops, the lumen consequentially narrows as the necrotic core of the atheroma alters the structure of the blood vessel irreversibly. A narrower lumen increases blood pressure, putting more strain on the blood vessel and on the plaque. On top of this, inflammatory bodies continue to erode and disrupt the plaque, increasing the likelihood of rupture. Upon rupture, contents of the necrotic core and fragments of the plaque are released freely into the blood vessels and are the leading cause of thrombosis or thrombo-embolism. (Figure made with Biorender.com).

FIGURE 3

FPR2 Signalling Pathways. The binding of the FPR2 receptor agonist, LXA₄, has a number of different effects which promote an anti-inflammatory or pro-resolving chain of events. As a receptor agonist, binding of LXA₄ to FPR2 prevents the binding of other pro-inflammatory mediators to the receptor via pro-inflammatory agonist desensitisation and subsequent internalisation. Downstream of this internalisation, NF-κB is inhibited and as a result, pro-inflammatory cytokine transcription and translation are reduced, thus attenuating their release. Furthermore, internal calcium free ions are released primarily through the endoplasmic reticulum stores. This increased intracellular calcium flux promotes the generation of ROS through protein kinase C activation. The production of ROS increases the conversion of circulating LDL to ox-LDL and thus augmenting macrophage and neutrophil attraction to the site of inflammation, which in turn improves phagocytosis and efferocytosis. Finally, the TGF-β pathway is inhibited via a reduction in the expression of its receptor, TGF-βR, which plays a number of key roles, both athero-protective, and atherogenic, modulating the stiffening of arteries and blood vessels in later stages of atherosclerosis. (Broken arrows/inhibitors indicate a downstream effect, whereas a solid arrow/inhibitor indicates a direct effect) (Figure made with Biorender.com).