биохимия атеросклероза

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TNF-α promote VSMC proliferation and migration as well as the proliferation of the endothelium itself [78]. Moreover, other factors like loss of NO, increased platelet adherence, release of vasoactive agents (thromboxanes, ET-1, AngII), and increased expression of MMP leads to enhanced local vasoconstriction, fibroblast-mediated collagen synthesis, and matrix deposition in the endothelium [84–88]. Especially, MMP secreted by the endothelium and other immune cells play an important role in the degradation of extracellular matrix that lends stability to the plaque’s fibrous cap. MMP-mediated areas of fissuring or ulceration that subsequently develop in advanced atherosclerotic plaques are particularly vulnerable to platelet-associated vascular hemorrhage, rupture, thrombosis, embolization, and occlusion [78, 89]. Thus, inflammatory molecules play an important role in mediating the phases of the onset and progression of atherosclerosis.

Endothelial Dysfunction: Role of Dietary fats

The development of endothelial dysfunction and its progression to atherosclerosis is a multistep process, where each step is regulated by an array of vasoactive molecules, growth factors, cytokines, and ROS. This multifactorial etiology has known to be modulated through diet. This has sparked an interest in the role of nutritional factors in modulating endothelial function. However, to derive maximum health benefits from dietary fats, it is necessary to possess knowledge of the varied effects of different dietary fats on processes like endothelial dysfunction and atherosclerosis.

Saturated Fatty Acids

Excess consumption of saturated fatty acids (SFA) has always been associated with increased CHD [90–94]. Furthermore, there are numerous epidemiological studies that relate high SFA intake with increased endothelial dysfunction. However, the mechanisms employed by SFA to induce these abnormalities are not completely understood. One of the possible mechanisms is the elevation of plasma LDL levels [95]. SFA like lauric (12:0), myristic (14:0), and palmitic (16:0) acids are associated with increased plasma LDL levels [96, 97], thereby causing endothelial dysfunction. Both in vitro and in vivo studies in animals have shown that endothelial function may be abnormal within a few hours of exposure to increased levels of LDL cholesterol [98, 99]. Furthermore, increased LDL levels increase their susceptibility to oxidation, resulting in the formation of Ox LDL that affects endothelial function, as discussed in the earlier sections.

In addition to altering the plasma LDL levels, some of the SFA may also affect thrombosis. Stearic acid (18:0) has been shown to induce thrombosis in experimental animals via affecting platelet activity and the activation of coagulation [100]. There is further evidence from human studies that increased

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[112]. Certain studies have examined the relation between the intake of trans-fatty acids and plasma concentrations of biomarkers of inflammation and endothelial dysfunction [109, 113]. One of these studies indicated a positive correlation between plasma concentrations of IL-6, soluble ICAM- 1, soluble VCAM-1, E-selectin, and dietary trans-fat intake [109]. In addition, trans-fatty acids can inhibit enzymes of the eicosanoid metabolism, which further results in disturbed prostaglandin balance and increased thrombosis [114].

Monounsaturated Fatty Acids

Consumption of monounsaturated fatty acids (MUFA) has been linked with a reduced incidence of CHD [115, 116]. Among these, oleic acid (18:1) has been shown to reduce plasma LDL levels as well as its oxidative modification [117, 118]. MUFA can decrease dietary thrombogenic potential when substituted for SFA diets. However, it has never been reported to have antithrombotic effects on its own. One study aimed at analyzing the effects of MUFA on the expression of VCAM-1 revealed an increased inhibition of VCAM-1 activity [107]. Thus, the presence of even one double bond appears to be crucial to the effects of modulation of endothelial–leukocyte interactions. It was also predicted that the substitution of SFA in membrane phospholipids by MUFA, renders the endothelial cells less responsive to the stimulation of cytokines [119]. Also, human studies have shown that a high MUFA diet possesses potential beneficial effect on platelet aggregation and postprandial activation of factor VII [120]. However, oleic acid has also been shown to inhibit endothelial NO synthesis by decreasing eNOS activity, resulting in impaired endothelium-dependent vasorelaxation [121] (Fig. 23.4).

Polyunsaturated Fatty Acids

Dietary polyunsaturated fatty acids (PUFA) comprise n−6 and n−3 PUFA. N−6 PUFAs are derived from linoleic acid (LA, 18:2), consumption of which has been promoted in the Western diets based on its plasma LDL lowering properties [122]. However, dietary LA is now being recognized to favor oxidative modification of LDL [123, 124], increase platelet response to aggregation [125], and suppress the immune system [126]. Furthermore, it is known to play an important role in the development of endothelial dysfunction. It can cause an imbalance in cellular oxidative stress of the endothelium thereby resulting in the activation of certain stress responsive transcription factors, inflammatory cytokine production, and the expression of adhesion molecules [127]. An increased consumption of n−6 PUFA is also known to result in the accumulation of AA, which results in the enhanced production of eicosanoids. In small quantities, the eicosanoids from AA are biologically active, however, they can contribute to the formation of thrombi and atheromas when formed in large quantities. Thus, high dietary intake of n−6 fatty

acids shifts the physiological state to prothrombotic and proaggregatory, resulting in progression of atherosclerosis. [122].

In contrast to LA, α linolenic acid (ALA, n−3, 18:3) is known to reduce endothelial dysfunction and CHD [127]. ALA is the precursor for other important n−3 PUFA, i.e., eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6). Fish or fish oil serve as a rich source of these n−3 fatty acids. Several studies have reported an association between fish oil consumption and protection against CHD [128–132]. The primary mechanism by which n−3 fatty acids are beneficial in cardiovascular disorders is by decreasing plasma LDL levels. However, their role in affecting the oxidative status of LDL is not clear. There are conflicting results among studies on the susceptibility of LDL to oxidation due to n−3 PUFA supplementation. There are some human studies which reported enhanced oxidation of LDL [133, 134], whereas some other studies observed no effect of dietary n−3 PUFA on LDL oxidation [135–137]. It, therefore, remains to be established whether LDL oxidative status in vivo is affected by n−3 fatty acids [138].

In addition to the hypolipidemic effects, EPA has been shown to increase endothelium-dependent relaxation in vitro through multiple mechanisms, including an increase in intracellular Ca2+ concentration and translocation of eNOS [139, 140]. Similarly, treatment of isolated rat aortic rings with DHA was shown to enhance NO synthesis in endothelial cells and relaxation of VSMC [141] (Fig. 23.4).

N−3 fatty acids have also been shown to mediate anti-inflammatory effects by decreasing the expression of adhesion molecules and cytokines, thus affecting leukocyte–endothelium interactions. N−3 fatty acids are known to inhibit the synthesis and release of proinflammatory cytokines such as TNF- α, IL-1, and IL-2 that are released during the early course of ischemic heart diseases [142]. Mice fed fish oil were reported to have lower plasma concentrations of TNF-α, IL-1β, and IL-6 following endotoxin injection than mice fed safflower oil [143]. An anti-inflammatory cytokine IL-10 has been shown to be upregulated by n−3 fatty acids [144]. There are some studies, which demonstrate that n−3 fatty acids can further alter the metabolism of adhesion molecules such as VCAM-1, E-selectin, and ICAM-1 [138, 145]. One study reported that supplementation with a moderate dose of fish oil (1.2 g EPA+ DHA per day) for 12 weeks decreased plasma levels of soluble VCAM-1 in older human subjects [146]. Fish oil has further been shown to increase plasma soluble E-selectin [147]. In vitro studies have highlighted the potential for n−3 PUFA to modulate the expression of adhesion molecules by some cell types. Murine peritoneal macrophages were reported to show less adherent properties when cultured in the presence of EPA or DHA [148]. Similarly, human monocytes revealed a reduction in the expression of ICAM-1 when incubated with EPA, while DHA had no effect [149].

N−3 PUFAs are known to protect the cells from oxidative damage. It is proposed that long chain PUFA can scavenge the ROS undergoing selfperoxidation, thereby preventing the formation of hydrogen peroxide, which

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mediates cell activation due to oxidative stress [150]. Alternatively, long-chain PUFA can induce the expression of antioxidant enzymes like glutathione peroxidase, superoxide dismutase, and catalase, which maintain the oxidative balance of the cells [151]. Therefore, decreased expression and altered metabolism of adhesion, inflammatory, and antioxidant molecules caused by fish oil results in reduced platelet aggregation and their binding to the endothelial cells, ultimately resulting in an antiatherogenic phenotype.

Another potential antiatherogenic mechanism employed by n−3 fatty acids is their interference with the AA cascade that generates a wide variety of eicosanoids. When ingested, EPA and DHA can partially replace AA in cell membranes of platelets, erythrocytes, neutrophils, monocytes, and liver cells [122]. In addition, EPA and DHA are known to be the competitive inhibitors of COX, which results in reduced production of AA-derived eicosanoids [152, 153]. As a result, ingestion of EPA and DHA from fish or fish oil leads to an increased production of total prostacyclin by increasing PGI3, which is known to promote vasodilation and reduce platelet aggregation. In addition, n−3 fatty acids reduce the production of thromboxane A2, known to promote platelet aggregation and vasoconstriction. This is associated with an increase in thromboxane A3, which is a relatively weak vasoconstrictor [154]. N−3 fatty acids also affect the inflammatory processes by decreasing leukotriene B4, and simultaneously increasing leukotriene B5 [155, 156].

N−3 fatty acids are further known to possess a novel stabilizing effect on the myocardium itself, resulting in lowering the incidence of arrhythmias [138]. This seems to be due to the ability of n−3 fatty acids to prevent calcium overload by maintaining the activity of L-type calcium channels during periods of stress [157], and to increase the activity of cardiac microsomal Ca2+/Mg2+-ATPase [158]. In addition, n−3 fatty acids (including ALA) are potent inhibitors of voltage-gated sodium channels in cultured neonatal cardiac myocytes, which may contribute to a reduction in arrhythmias [152].

Conclusions

Atherosclerosis is known to be the leading cause of morbidity and mortality worldwide. It is a complex disease that involves exploitation of various cellular pathways for its progression. However, there is increasing evidence that violation of normal endothelial function is the primary event for the initiation of these disorders. Endothelium not only serves as a barrier between blood and the interstitium, it further maintains the cardiovascular health by regulating vascular tone, anti-inflammatory, and anti-aggregatory pathways. Endothelial dysfunction caused due to injury or any pathophysiological stimuli renders it susceptible to the development of atherosclerosis and CHD. Oxidative stress and inflammation are known to play a key role in the development of endothelial dysfunction. Various dietary fats exert different effects on the endothelial function. While, increased consumption of SFA and trans-fatty acids has been

shown to have deleterious effects, MUFA and n−3 PUFA are known to possess cardioprotective effects. Although individual effects of dietary fats are well established, the complete understanding of the employed molecular mechanisms is still lacking. It is crucial to advance our knowledge in this area, as this will not only provide us with primary nutritional management of these disorders, but will further allow the secondary control of these disorders.

Acknowledgments: Research in our laboratory is funded by the Heart and Stroke Foundation of Canada, Natural Sciences and Engineering Research Council (NSERC), Canadian Institutes of Health Research (CIHR), and Canadian Innovation Fund (CFI). SKC is a CIHR New Investigator.

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