the role of PAF-R on atherosclerosis and how food components can inhibit it

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this post is from a recent review article of our team: Targeting the Platelet-Activating Factor Receptor (PAF-R): Antithrombotic and Anti-Atherosclerotic Nutrients

Cardiovascular diseases

Atherosclerotic cardiovascular diseases (CVD) are the leading cause of morbidity and mortality globally [1]. Various factors contribute to the development of atherosclerosis, but evidence in recent decades has demonstrated that nutrition plays a pivotal role in the prevention of atherosclerosis and other chronic inflammatory conditions including diabetes and obesity [2,3]. Hence there is a requirement to research the effects of diets and food components on cardiovascular health.
Atherosclerosis is a progressive inflammatory disease responsible for the development of atherothrombotic complications including myocardial infarction, peripheral artery disease, and ischaemic or transient stroke among other cardiac manifestations [4,5]. Atherosclerosis develops through several steps including endothelial dysfunction followed by the deposition of lipids in the intima, which accumulate in the lining of blood vessels. These lipids are then engulfed by macrophages, which eventually undergo apoptosis forming foam cells and a necrotic core that leads to the development of the characteristic lesions or fatty streaks in blood vessels. Erosion of these lesions or plaques causes microruptures that activate platelets causing fibrin netting and platelet aggregates to form on the inner walls of arteries, thus leading to the narrowing of blood vessels affecting blood supply [6]. With time, the lumen may narrow and erode further causing plaque rupture, leading to a major cardiovascular event such as myocardial infarction or stroke. The main mechanistic events that lead to these events are characterised by persistent low-grade inflammation [5].

Inflammation and cardiovascular diseases

However, inflammation is a necessary physiological response of the innate immune system, and its main role is to maintain a constant internal environment despite being subjected to constantly changing environmental pressures. These can include mechanical, physical, chemical, infectious, immunological, or reactive natural adverse events. The inflammatory response seeks to diminish and/or minimize the agents that causes tissue damage, promote adequate wound healing, and restore tissue homeostasis. However, if the inflammatory response fails to resolve owing to the persistence of the triggering factors or poor restoration of the original tissue, a prolonged underlying inflammatory process arises, leading to increased tissue dysfunction and adverse effects. At the molecular and cellular level, it has been postulated that endothelial dysfunction leading to systemic inflammation appears to be the primary underlying mechanistic factor in the onset and progression of atherosclerosis [7]. Endothelial dysfunction is often defined by an inflammatory microenvironment that acts on leukocytes and endothelial cells via interactions with other immune cells such as T lymphocytes, mast cells, dendritic cells (DC), and platelets [8].

Platelets and cardiovascular diseases

Platelets play a key role in the onset and development of atherosclerosis [9,10,11,12,13]. Platelets also orchestrate the development of obstructive thrombi in the latter stages of the atherosclerotic process in response to plaque rupture through the sequential processes of haemostatic responses to vascular injury such as initiation, extension, and stabilization [14]. Each of these stages contains pro-haemostatic molecular mechanisms, in balance with anti-haemostatic processes, which restrict the reaction to the damage site and prevent inappropriate vascular occlusion. The molecular players involved in the initiation process include adhesion molecules, signalling ligands, and their associated platelet surface receptors [15]. Strong inflammatory and prothrombotic mediators such as platelet-activating factor (PAF) play pivotal roles in these processes, particularly in the activation of platelets [16]. Indeed, PAF and its receptor have previously been investigated as a pharmaceutical target for some inflammatory conditions including asthma and sepsis with limited success to date. They have also been implicated in many of the key processes that lead to the development of atherosclerosis. However, researchers over the years have postulated that dietary PAF-R antagonists may affect PAF-related signalling and inflammatory pathways [7,17,18]. This has opened several avenues of research that aim to investigate certain dietary patterns such as the Mediterranean diet, which is thought to offer protection from atherosclerotic cardiovascular disease and other inflammatory diseases due to a high concentration of these compounds in the diet [18,19]. In this review, we examine the role of various nutrients and their effects on PAF and its receptor PAF-R and how attenuating this inflammatory and thrombotic pathway may contribute to atherosclerosis prevention via altering one’s diet. It is also important to recognise that while this review largely focusses on the relationship between PAF and the PAF-R, there are also ongoing developments in cardiovascular research relating to the metabolic enzymes of PAF, which have been discussed at length elsewhere [7,20].


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