Vascular System: Role of Selenium in Vascular Diseases

Abstract

The trace element selenium is crucial for cellular defense against oxidative stress and inflammatory reactions. Balanced selenium levels are important for the vascular system, whereas dysregulation can damage vascular reactivity. Reports have also supported the strong relationship between oxidative stress and vascular inflammation, which are induced by either the overproduction of reactive oxygen species (ROS) or the lack of antioxidant defense proteins. The damage of vascular smooth muscle and endothelium layer are frequently linked to vascular disorders such as hypertension, hypercholesterolemia, and atherosclerosis. Vascular diseases can result in life-threatening serious cardiovascular complications, such as blood clots, heart attack, and stroke. Selenium levels are crucial for preventing vascular damage; however, either low or extremely high amounts of selenium intake may contribute to the pathophysiology of vascular disorders. Selenoproteins are proteins such as glutathione peroxidase containing selenium in the form of the 21st amino acid, selenocysteine. Selenoproteins have the capacity to protect vascular smooth muscle and endothelium by lowering harmful ROS, which allows them to regulate normal vascular functions including vasoreactivity. The current chapter’s goal was to carry out a thorough evaluation of the literature on the connection between selenium and vascular disorders.

1. Introduction

Selenium is a cofactor of enzymes that are responsible for antioxidant protection in the body. It is abundant in the environment at varying levels and plays an important role in the regulation of inflammatory processes in the body [1]. Adequate bioavailable levels of selenium in the organism are functionally important for many aspects of human biology, including the cardiovascular system, central nervous system, male reproductive biology, endocrine system, muscle function, and immunity [2]. Selenium is an essential component of selenoproteins, which play an important role in a variety of biological functions including antioxidant defense, thyroid hormone formation, DNA synthesis, fertility, and reproduction [3]. Many selenoproteins have been identified in the organism, including glutathione peroxidases (GPXs), thioredoxin reductase (TrxR), iodothyronine deiodinase, selenoprotein P, and selenoprotein W [4]. GPXs of the selenoprotein family are antioxidants that play an important role in oxidative stress and vascular tissue damage [5]. When the oxidative-antioxidant balance function is disrupted as a result of oxidative stress, several pathogenic processes can occur in vascular system. Oxidative stress and the formation of reactive oxygen species (ROS) contribute to the progression of tissue injury by activating the inflammatory response via the release of proinflammatory cytokines and the accumulation of inflammatory cells in tissues [6]. Endothelial dysfunction is important in the development of vascular diseases, and selenium reduces endothelial damage and prevents disruption of endothelial-dependent relaxation [7]. While a lack of selenium can lead to a variety of diseases, an excess of selenium can be toxic and result in the selenosis condition [8]. Low or excessive selenium consumption has been linked to different vascular diseases such as hypertension, hypercholesterolemia, and atherosclerosis [9]. The fundamental pharmacological, physiological, and pathophysiological properties of selenium in vascular disease are presented in this chapter.

2. The relationship between selenium and vascular diseases

Vascular smooth muscle (VSM) tone in the arterial vessels determines peripheral vascular resistance and blood pressure. Endothelial cells regulate VSM tone and subsequently blood flow by producing and releasing relaxants such as nitric oxide and contractile substances such as endothelin. The defective function of VSM and endothelial layer are commonly associated with impaired vascular responses [10]. The coexistence of dyslipidemia and oxidative stress is a major risk factor for the development of vascular diseases such as atherosclerosis and hypertension [11]. VSM and endothelial cells function properly and maintain an appropriate oxidant/antioxidant balance when selenium and selenoproteins are present in the proper amounts [12]. A sufficient concentration of selenium-dependent GPXs is required to maintain an active endogenous antioxidant system, which prevents vascular diseases caused by hypertension, hypercholesterolemia, and atherosclerosis [13]. Overall, the GPX family is one of the best-studied selenoprotein families in cardiovascular biology. There are five different types of GPX isoforms, with GPx-3 being the only one found in the extracellular space [14]. GPx-3 deficiency causes a prothrombotic state and vascular dysfunction, which promotes platelet-dependent arterial thrombosis [9]. The link between low selenium intake and cardiovascular pathologies is due to increased oxidative stress and its consequences in the development of non-infectious vascular diseases [15]. Decreased amount of selenium in the body is associated with an increase in adhesion molecules and a decrease in the expression of selenoproteins despite endothelial cell integrity and function [16]. A potentially harmful relationship was discovered between high selenium levels and carotid wall thickening, despite a long-term vascular protective effect between arterial stiffness and blood pressure in people with normal selenium levels [17]. All of this points to a significant relationship between selenium and the vascular system. Table 1 summarizes studies demonstrating the effect of selenium on vascular diseases.

Disease	Species	Method	Conclusion	References
Hypertension	Human	Selenium deficiency	Higher risk in pregnancy-induced hypertension	[18]
Hypertension	Human	Higher selenium levels	Lower risk in ischemic stroke	[19]
Hypertension	Human	Higher selenium levels	Selenium protects vascular function	[20]
Hypertension	Human	Higher selenium levels	Higher prevalence of hypertension	[21]
Hypertension	Rat	Selenium deficiency	Increase in AT1 receptors and blood pressure	[22]
Hypertension	Rat	Higher selenium levels	Increase in systolic blood pressure	[23]
Dyslipidemia	Human	Selenium deficiency	Low HDL levels, high LDL levels	[24]
Hyperlipidemia	Human	Selenium deficiency	Selenium may prevent hyperlipidemia	[25]
Dyslipidemia and atherosclerosis	Rabbit	0.5% dietary cholesterol-induced dyslipidemic rabbits	Co-supplementation of vitamin K2 and selenium improved metabolic profile and atherosclerosis	[26]
Hyperlipidemia	Mice	Selenium nanoparticles	Selenium reduces hyperlipidemia and vascular injury	[27]
Hyperlipidemia	Mice	High fat diet-induced dyslipidemia	Selenium-rich Cordyceps militaris polysaccharides could prevent hyperlipidemia	[28]
Endothelial dysfunction	Rat	Homocysteine-induced endothelial dysfunction and apoptosis	Selenium protects against homocysteine-induced dysfunction and apoptosis of endothelial cells.	[7]
Endothelial dysfunction	Rat	Streptozotocin-induced diabetic aorta	Selenium improved vascular responses and endothelial dysfunction	[29]

Table 1.

Selenium research in vascular disease.

2.1 Hypertension

Because of its high prevalence and associated risks of cardiovascular and kidney disease, hypertension is a major public health issue worldwide [30]. Endothelial dysfunction, inflammation, hypertrophy, apoptosis, cell migration, fibrosis, and angiogenesis have all been linked to vascular remodeling in hypertension [31]. Ozturk et al. reported that selenium reduced the disruption of endothelium-dependent vasorelaxation in the diabetic aorta and improved vascular responses and endothelial dysfunction in diabetes by regulating antioxidant enzymes and nitric oxide release [29]. Many studies have been conducted to investigate the relationship between hypertension and low and high dietary selenium intake. Selenium deficiency in rats caused an increase in H2O2 production by decreasing GPx1 expression and increased renal angiotensin II type 1 receptor expression by increasing NF-κB activity, resulting in sodium retention and an increase in blood pressure [22]. It has been reported that men with antioxidant selenium deficiency (selenium concentration lower than 20 μg/l) have higher blood pressure and a higher risk of developing hypertension [32]. Obese elderly people may require more antioxidants, particularly selenium, to counteract the increased oxidative stress that leads to vascular oxidative dysfunction [33]. Increased plasma selenium levels were found to be significantly associated with a lower risk of first stroke and ischemic stroke in hypertensive adults [19]. Selenium has been shown to lower the incidence of mercury-related hypertension and protect vascular function among Inuit in Canada [20]. Lower serum selenium levels in early healthy pregnancy were linked to an increased risk of pregnancy-induced hypertension and served as a risk marker for this potentially dangerous disease [18]. High selenium intake appeared to be a blood pressure protective factor, particularly in people living in low selenium areas [34]. On the contrary, some studies have found that a high selenium intake is associated with vascular system damage. Increasing selenium levels above the recommended daily intake is not beneficial for vascular health and may even cause hypertension, hyperlipidemia, and diabetes [35]. According to Laclaustra et al., there is a strong correlation between elevated serum selenium levels and a high prevalence of hypertension in the US population [21]. Similarly, long-term selenium supplementation (2 and 6 mg/L) resulted in a significant increase in systolic blood pressure in rats after 42 days [23]. The cause of hypertension caused by high selenium intake may be related to endothelial dysfunction via a mechanism involving cell death mediated by ROS production induced by endoplasmic reticulum stress [36]. While a high selenium intake is generally beneficial through an antioxidant mechanism, it may also be a factor in the development of hypertension.

2.2 Hypercholesterolemia and atherosclerosis

Hyperlipidemia, caused by hypercholesterolemia and/or hypertriglyceridemia, is a critical condition that plays a significant role in the pathogenesis of atherosclerosis [37]. Apoptotic VSM cells, which are found in advanced atherosclerosis, cause plaque instability and rupture, which results in thrombosis and the clinical symptoms of a heart attack or stroke [38]. Selenoproteins can destroy cholesterol that has accumulated in the vascular lumen. Inadequate plasma selenium levels can lead to vascular disease by lowering selenoprotein levels [39]. Optimal Se uptake prevents atherosclerosis by reducing oxidative stress, inflammation, endothelial dysfunction, vascular cell apoptosis, and vascular calcification [40]. Selenium supplementation increases GPX1, GPX4, and TRXR1 expression and activity in vascular endothelial or smooth muscle cells. As a result, it prevents oxidative stress, cell damage, and apoptosis caused by oxidized low-density lipoprotein (LDL), a cytotoxic hydroxylated cholesterol derivative found in human blood, cells, tissues, and atherosclerotic plaques [41]. The selenoenzyme GPX uses GSH as an electron donor to neutralize hydroperoxide and protects against arsenic-induced atherosclerosis in a mouse model [42]. In healthy young subjects, a negative relationship was found between serum triglycerides and sialic acid, an inflammation marker, and dietary selenium intake [43]. Experimental studies have shown that selenium is used in combination with other substances and improves hyperlipidemia more strongly. It was reported that concomitant administration of vitamin K2 and selenium improved metabolic function, markers of cardiovascular health, and atherosclerosis in dyslipidemic rabbits [26]. Yu et al. also found that consuming a high dose of selenium-rich Cordyceps militaris polysaccharides could prevent high fat diet-induced dyslipidemia and dysbiosis of the gut microbiota, and that it could be used as a functional food [28]. Vascular dysfunction occurs in patients with a high selenium deficiency, and there is a positive correlation between HDL and selenium in dyslipidemic patients [24]. Selenium levels tend to decrease with age, and high selenium status may be beneficial in preventing hyperlipidemia in young adult females [25]. Selenium nanoparticles could significantly reduce hyperlipidemia and vascular injury in apolipoprotein E deficient mice, possibly by regulating cholesterol metabolism and reducing oxidative stress via antioxidant selenoenzymes/selenoproteins, and could be a potential candidate for atherosclerosis prevention [27].

3. Conclusions

These findings suggest that adequate selenium intake may contribute to preventing the development of hypertension, hyperlipidemia, and atherosclerosis by reducing oxidative stress and inflammation associated with vascular diseases. Furthermore, the findings emphasize the importance of consuming or supplementing with an adequate amount of selenium to optimize vascular system function. Selenium appears to have both a protective and a therapeutic role in the vascular dysfunction, and more research on the effect of selenium on the vascular system is required. As a result of the recent studies, it is understood that people living in low selenium-containing regions should be protected from vascular damage by taking selenium supplements. Selenium, which regulates blood pressure and reduces atherosclerosis caused by hyperlipidemia, could be used as a potential pharmacological agent in the prevention of vascular diseases in the near future.