Fucoidans as a Potential Nutraceutical in Combating Atherosclerotic Cardiovascular Diseases

The base of atherosclerotic cardiovascular diseases (ACVD) is the triad dyslipidemia, inflammation and thrombosis. Fucoidans are sulfated polysaccharides components from brown algae Phaeophyceae class related to several biological activities. In this article, we discuss some “ in vitro ” and experimental studies describing actions of fucoidan that could be beneficial in controlling ACVD. Nonetheless, clinical studies are still scarce in the literature. It has been shown that fucoidans reduce blood lipids, increase LDL receptor and reduce scavenger receptors, impair migration and activation of immune cells and cytokine production and also reduce platelet aggregation and increase fibrinolysis. Fucoidan is a potential nutraceutical that could be useful as an adjuvant in preventing or treating ACVD. Nonetheless, future clinical studies are needed to confirm these effects in humans. Abbreviations: AP-1: Protein-1; Cardiovascular Diseases; C-Jun N-Terminal Oxygenase Hydroxy-Methyl-Glutaryl Nitric Synthase; Metalloproteinases; SOD1:


Introduction
Atherosclerotic cardiovascular diseases (ACVD) are one of the most relevant world health problems, accounting for more than 30% of all global deaths [1]. It englobes primary acute myocardial infarction, but also ischemic stroke, intermittent claudication due to obstruction of peripherical arteries and aorta aneurysm [2].
The base of ACVD is the triad dyslipidemia, inflammation, and thrombosis. High levels of low-density lipoprotein (LDL) contributes to endothelial dysfunction and inflammation, culminating in atherothrombosis, blood flow obstruction and tissue ischemia/ necrosis. Several risk factors, including diabetes, smoking, sedentary lifestyle, familial history, obesity and hypertension may induce or accelerate endothelial injury, contributing to the progression of atherosclerosis [2].
LDL is the primary causal factor associated with atherosclerosis.
In the early phase of atherogenesis, the excess of blood LDL passes through the dysfunctional endothelium and remains in the intimal layer or forms aggregates with proteoglycans. Abnormal LDL, mainly oxidized or glycated (oxLDL) can also promote or accelerate this process [3]. Endothelial activation by oxLDL is characterized by the higher expression of adhesion molecules, secretion of inflammatory mediators and leukocyte recruitment, mainly monocytes, to the lesion site [4]. In the arterial intima layer, recruited monocytes differentiate into macrophages and uptake oxLDL by scavenger receptors (such as CD36 and SRA), transforming into foam cell, the primary atherosclerotic lesion. LDL receptor related protein (LRP) in the surface of smooth muscle cells (SMC) (migrated from media layer) can bind LDL-proteoglycan aggregates, also generating foam cells. The continuous and unregulated oxLDL endocytosis will lead to the expansion of foam cells, forming the atheroma. As the plaque progresses, new events contribute to the lipid-rich necrotic core formation such as local hypoxia, intraplaque angiogenesis and thrombosis, T and B cell migration, cytokine production and deposition of apoptotic debris with inefficient efferocytosis [5].
Lesions are covered by a fibrous cap formed by the extracellular matrix produced by smooth muscle cells that stabilize the atheroma [6]. Nonetheless, the production of matrix metalloproteinases (mainly MMP-2 and MMP-9) by macrophage and the inflammatory mediators (such as interferon-gamma) released by T cells may degrade or inhibit the production of the extracellular matrix, causing plaque vulnerability with subsequent rupture [7].
Plaque rupture propitiates the contact of thrombogenic components (such as tissue factor) and other intraplaque material with blood, leading to thrombus formation, arterial obstruction, and ischemia of the tissue drained by that artery. Despite the increasing number of drugs to prevent and treat atherosclerosis, diet still integrates the first-line treatment [8]. Moreover, phytotherapeuticagents and nutraceuticals could be used as adjuvant therapy, permitting a safer and longer use compared to several drugs [9]. In the context of atherosclerosis, fucoidans could be an exciting therapeutic adjuvant due to several actions that can interfere with atherosclerosis progression [10,11]. Here we will discuss the main biological activities of fucoidan that make it a potential nutraceutical helping the management of ACVD.

General Characteristics of Fucoidans
Oceans and seas are sources of food for the whole world population due to the abundance of biological and natural resources.
The diversity of marine species of fish, mollusks, crustaceans, and others offers multiple nutrients sources for a healthy diet. Seaweeds are, in many countries, a source of dietary nutrients and also a nutraceutical agent. Fucoidans are algae components that have been studied and related to several biological activities. Fucoidan is one of several marine sulfated polysaccharides, called "fucans" and mainly found in cell walls and the intercellular spaces of the brown algae from Phaeophyceae class [12]. The characteristics of fucoidan are also influenced by the purification processes. The lack of a standardized purification procedure leads to differences in the structure of the extracted polysaccharide. Despite these structural differences, fucoidan has been used as a nutraceutical supplement in several countries. The biological properties of fucoidans are determined by characteristics, such as molecular weight, structure, frequency, the position of sulfate groups, and the organization of sulfated domains [15].
Several "in vitro" and "in vivo" studies have described the fucoidan activities which could influence atherosclerosis development.
Although studies of the biological activities of fucoidans have been conducted using molecules from different algae, we are presenting their origins and related activities in Table 1   induced LDL oxidation compared to high molecular weight ones [28]. In an "in vivo" study using LDL receptor knockout (LDLR-/-) mice, the oxLDL receptor (LOX-1) and reactive oxygen species (ROS) related protein were negatively regulated in the aorta after fucoidan supplementation [51]. These results suggest that fucoidan reduces oxidative stress and atherogenesis in animal models.
Similar results were obtained in streptozotocin-induced diabetic mice that presented a lower ROS production in aorta smooth muscle cells after fucoidan treatment [52]. The mechanism may be linked to the inhibition of the Mitogen Activated Protein kinases (MAPK) and Nrf2/ERK signaling that mediates the expressions of HO-1 (heme oxygenase 1) and SOD1 (superoxide dismutase 1) [53,54].

Fucoidan as an Anti-Inflammatory Agent.
Fucoidans are potent inhibitors of leukocyte migration and platelet activation due to their interaction with L and P-selectins, acting as a "selectin blocker" [55]. P-selectin is found in the surface of activated platelets as well as activated endothelium [56]. The adhesion of leukocytes (neutrophils and monocytes) to the activated vascular endothelium and the adhesion of leukocytes to activated platelets are facilitated by selectins [57]. Fucoidan probably acts similarly to heparan sulfate, presenting a spatial structure of