**3. Stress, dyslipidemia and atherosclerosis: Putative mechanisms**

Atherogenic dyslipidemia is a major underlying cause of the development of atherosclerosis, which is an inflammatory disease (Mullick et al., 2006; Sheril et al., 2009). Since the stress-induced atherogenic lipid profile potentiates the effects of dietary and genetic factors in atherogenesis (Brindley et al., 1993), stress has been recognized as a risk factor for atherosclerosis (Kyrou & Tsigos, 2009; Shively et al., 2009). However, despite the association between dyslipidemia and atherosclerosis, many individuals develop severe atherosclerotic lesions associated with low serum lipid concentration, and others develop far more severe atherosclerosis than would be expected on the basis of a modest elevation of serum lipids (Kaplan et al., 1983). In this context, other effects of stress, not related specifically to dyslipidemia, are also involved in atherogenesis (Bierhaus et al., 2003; Gu et al., 2009) and approximately 40% of cases without known causal factor, have been attributed to stressful situations (Black, 2002).

Dyslipidemia Induced by Stress 373

mitogen-activated protein kinase pathway in endothelial cells. Impairment of the phosphatidylinositol 3-kinase pathway reduces eNOS activity, and accentuates free fatty acid-evoked oxidative stress. These effects decrease NO bioavailability and promote an imbalance between vasoconstriction and vasodilation (Cersosim & DeFronzo, 2006; Muniyappa & Quon, 2007) predisposing the individual to atherosclerosis and arterial hypertension. In addition insulin resistance increases the reactive oxygen species, reducing

Morphological changes in blood vessels are also associated with atherosclerosis. The increase in intima media thickness (IMT) in the carotid artery has been used as a marker of target organ damage in human hypertension (Sierra & de la Sierra, 2008). In experimental studies, the IMT of the aorta observed in stressed rats (Okruhlicová et al., 2008) was related to the atherogenic effects of stress. In healthy blood vessels, NO produced by the endothelium maintains the mitogenic quiescence of smooth muscle cells. Decreased NO bioavailability induced by stress-related glucocorticoid levels or -insulin resistance results in the loss of this effect and consequently vessel wall hypertrophy may occur (Costa & Assreuy, 2005). In fact, it has been observed that rats submitted to chronic mild unpredictable stress presented higher IMT and lower relaxation response to acetylcholine in the thoracic aorta, in comparison with non stressed animals. These effects were observed 15 days after the end of the stress protocol and were associated with insulin resistance and dyslipidemia. However, in this study, the dyslipidemia induced by the hypercaloric diet alone, did not promote morphological or functional changes in the thoracic aorta, or insulin

resistance evidencing the role of stress in pro-atherogenic effects (Neves et al., 2011).

NPY, a hormone known as orexigenic peptide, may also be involved in the atherogenic effects of stress. Some stressors such as cold and aggression, increase the release of NPY from sympathetic nerves (Kuo et al., 2007). The peripheral actions of NPY are stimulatory, synergizing with glucocorticoids and catecholamines to potentiate the stress response. It causes prolonged vasoconstriction, potentiating the effect of norepinephrine, induces hyperlipidemia, and vascular remodeling via smooth muscle cell proliferation, in addition to stimulating monocyte migration and activation (Kuo et al., 2007). NPY upregulates its Y2 receptors in a glucocorticoid-dependent manner in abdominal fat, consequently leading to abdominal obesity, hyperinsulinemia and dyslipidemia (Kuo et al., 2008). In blood vessels, Y1 and Y5 receptor activation promotes pro-atherogenic responses (Zukowska, 2005). In addition to all the above-mentioned mechanisms, the inflammatory process also forms part of the stress response (Black, 2003), and is pathophysiologically linked to atherosclerosis (van Oostrom et al., 2004). In the atherogenic process, the high level of catecholamines induced by stress stimulates endothelial permeability to the traffic of oxidized LDL. Once trapped in the endothelium of an artery, LDL can undergo progressive oxidation, cross the endothelial barrier, and be internalized by macrophages expressing scavenger receptors, leading to lipid peroxide formation and accumulation of cholesterol esters, culminating in foam cells formation (Ross, 1999; Singh & Mehta, 2003). Oxidized LDL upregulates the expression of adhesion molecules and secretion of chemokines, which contributes to the recruitment of circulating monocytes and leukocytes (Cersosimo & DeFronzo, 2006; Steinberg, 2002). One of the initial steps in the formation of atherosclerosis is the adhesion of monocytes to the endothelium, their entry into sub-endothelial space, followed by their differentiation into macrophages (Lamharzi et al., 2004). These cells are then responsible for taking up LDL and other particles, thereby starting the atherogenesis process (Lamharzi et al., 2004). In foam cell formation, the macrophages in the endothelial

eNOS activity (Muniyappa et al., 2008).

The atherogenic effects of stress include changes in nitric oxide (NO) and cytokine production, vascular smooth muscle mitogenesis, occurrence of insulin resistance, neuropeptide Y (NPY) actions and modulation of the renin-angiotensin system activity. These effects are directly and indirectly related to stress-induced dyslipidemia, as will be pointed out below.

The healthy endothelium provides a smooth barrier that limits the activation of proinflammatory factors, blocks the transfer of Apo-B 100-containing atherogenic lipid particles into subendothelial space, inhibits the release of chemokines and cytokines, and prevents platelet and monocyte adhesion to the vascular wall (Cersosimo & DeFronzo, 2006). A high amount of NO is produced by endothelial nitric oxide synthase (eNOS). It is a vasodilator, has antithrombogenic properties, is an inhibitor of smooth muscle cell proliferation and of leukocyte- and monocyte-adhesion (Badimón & Martínez-González, 2002; Sudano et al., 2006). Decrease in NO bioavailability is a key feature of endothelial dysfunction resulting in lower responses to vasodilator agents (Codoñer-Franch et al., 2011), and represents an early stage of atherosclerosis (Badimón & Martínez-González, 2002). Endothelial dysfunction contributes to the development and progression of atherosclerosis by favoring coagulation, inflammatory cell adhesion, imbalance between vasoconstriction and vasodilation, and by enhancing transendothelial transport of atherogenic particles (Cersosimo & DeFronzo, 2006).

High stress-induced glucocorticoid levels reduce the expression of guanosine triphosphate cyclohydrolase 1 messenger ribonucleic acid (mRNA), necessary for tetrahydrobiopterin cofactor (BH4) synthesis, which stabilizes eNOS (Mitchell et al., 2004). If BH4 levels decrease, endothelial eNOS becomes uncoupled and transfers electrons to molecular oxygen generating superoxide anions (Rizzo et al., 2009), which react avidly with NO to form peroxynitrites (Förstermann & Münzel, 2006), resulting in diminished NO bioavailability, and favoring the traffic of oxidized lipids across the endothelium. Associated with this injurious effect of glucorticoids, the high LDL levels induced by stress also decrease eNOS mRNA expression (Liao et al., 1995).

Considering dyslipidemia induced by stress, it has been reported that before structural changes appear, chronic elevations of cholesterol in the bloodstream are frequently associated with impaired endothelium-dependent NO production due to increased interaction between caveolin and eNOS (Feron et al., 1999). Caveolin proteins are expressed in the majority of the cell types that play a role in atherogenesis, including endothelial cells, macrophages, and smooth muscle cells (Frank & Lisanti, 2004). High levels of LDLcholesterol increase the caveolin concentration in endothelial cells (Feron et al., 1999), strengthen the calveolin-eNOS complex, and reduce the interaction between Ca2+ calmodulin and eNOS. These effects decrease eNOS translocation from caveolae to the cytoplasm and considerably diminish NO production (Feron et al., 1999; Frank & Lisanti, 2004). In addition, lipid peroxidation induced by stress also impairs nitric oxide production (NO), stimulates inflammatory response, and increases the traffic of inflammatory molecules and oxidized LDL to sub-endothelial space, leading to vascular endothelial dysfunction (Black, 2002; Black, 2003; Black & Garbutt, 2002; Rizzo et al., 2009).

Insulin resistance is also involved in the atherogenic effects of stress. Insulin stimulates NO production by the endothelium (Muniyappa & Quon, 2007). During chronic stress cortisolinduced insulin resistance (Black, 2002; Kyrou & Tsigos, 2009) decreases this effect, and endothelial dysfunction may occur. In addition, insulin resistance is associated with inhibition of the phosphatidylinositol 3-kinase pathway and over-stimulation of the

The atherogenic effects of stress include changes in nitric oxide (NO) and cytokine production, vascular smooth muscle mitogenesis, occurrence of insulin resistance, neuropeptide Y (NPY) actions and modulation of the renin-angiotensin system activity. These effects are directly and indirectly related to stress-induced dyslipidemia, as will be

The healthy endothelium provides a smooth barrier that limits the activation of proinflammatory factors, blocks the transfer of Apo-B 100-containing atherogenic lipid particles into subendothelial space, inhibits the release of chemokines and cytokines, and prevents platelet and monocyte adhesion to the vascular wall (Cersosimo & DeFronzo, 2006). A high amount of NO is produced by endothelial nitric oxide synthase (eNOS). It is a vasodilator, has antithrombogenic properties, is an inhibitor of smooth muscle cell proliferation and of leukocyte- and monocyte-adhesion (Badimón & Martínez-González, 2002; Sudano et al., 2006). Decrease in NO bioavailability is a key feature of endothelial dysfunction resulting in lower responses to vasodilator agents (Codoñer-Franch et al., 2011), and represents an early stage of atherosclerosis (Badimón & Martínez-González, 2002). Endothelial dysfunction contributes to the development and progression of atherosclerosis by favoring coagulation, inflammatory cell adhesion, imbalance between vasoconstriction and vasodilation, and by enhancing transendothelial transport of atherogenic particles

High stress-induced glucocorticoid levels reduce the expression of guanosine triphosphate cyclohydrolase 1 messenger ribonucleic acid (mRNA), necessary for tetrahydrobiopterin cofactor (BH4) synthesis, which stabilizes eNOS (Mitchell et al., 2004). If BH4 levels decrease, endothelial eNOS becomes uncoupled and transfers electrons to molecular oxygen generating superoxide anions (Rizzo et al., 2009), which react avidly with NO to form peroxynitrites (Förstermann & Münzel, 2006), resulting in diminished NO bioavailability, and favoring the traffic of oxidized lipids across the endothelium. Associated with this injurious effect of glucorticoids, the high LDL levels induced by stress also decrease eNOS

Considering dyslipidemia induced by stress, it has been reported that before structural changes appear, chronic elevations of cholesterol in the bloodstream are frequently associated with impaired endothelium-dependent NO production due to increased interaction between caveolin and eNOS (Feron et al., 1999). Caveolin proteins are expressed in the majority of the cell types that play a role in atherogenesis, including endothelial cells, macrophages, and smooth muscle cells (Frank & Lisanti, 2004). High levels of LDLcholesterol increase the caveolin concentration in endothelial cells (Feron et al., 1999), strengthen the calveolin-eNOS complex, and reduce the interaction between Ca2+ calmodulin and eNOS. These effects decrease eNOS translocation from caveolae to the cytoplasm and considerably diminish NO production (Feron et al., 1999; Frank & Lisanti, 2004). In addition, lipid peroxidation induced by stress also impairs nitric oxide production (NO), stimulates inflammatory response, and increases the traffic of inflammatory molecules and oxidized LDL to sub-endothelial space, leading to vascular endothelial

dysfunction (Black, 2002; Black, 2003; Black & Garbutt, 2002; Rizzo et al., 2009).

Insulin resistance is also involved in the atherogenic effects of stress. Insulin stimulates NO production by the endothelium (Muniyappa & Quon, 2007). During chronic stress cortisolinduced insulin resistance (Black, 2002; Kyrou & Tsigos, 2009) decreases this effect, and endothelial dysfunction may occur. In addition, insulin resistance is associated with inhibition of the phosphatidylinositol 3-kinase pathway and over-stimulation of the

pointed out below.

(Cersosimo & DeFronzo, 2006).

mRNA expression (Liao et al., 1995).

mitogen-activated protein kinase pathway in endothelial cells. Impairment of the phosphatidylinositol 3-kinase pathway reduces eNOS activity, and accentuates free fatty acid-evoked oxidative stress. These effects decrease NO bioavailability and promote an imbalance between vasoconstriction and vasodilation (Cersosim & DeFronzo, 2006; Muniyappa & Quon, 2007) predisposing the individual to atherosclerosis and arterial hypertension. In addition insulin resistance increases the reactive oxygen species, reducing eNOS activity (Muniyappa et al., 2008).

Morphological changes in blood vessels are also associated with atherosclerosis. The increase in intima media thickness (IMT) in the carotid artery has been used as a marker of target organ damage in human hypertension (Sierra & de la Sierra, 2008). In experimental studies, the IMT of the aorta observed in stressed rats (Okruhlicová et al., 2008) was related to the atherogenic effects of stress. In healthy blood vessels, NO produced by the endothelium maintains the mitogenic quiescence of smooth muscle cells. Decreased NO bioavailability induced by stress-related glucocorticoid levels or -insulin resistance results in the loss of this effect and consequently vessel wall hypertrophy may occur (Costa & Assreuy, 2005). In fact, it has been observed that rats submitted to chronic mild unpredictable stress presented higher IMT and lower relaxation response to acetylcholine in the thoracic aorta, in comparison with non stressed animals. These effects were observed 15 days after the end of the stress protocol and were associated with insulin resistance and dyslipidemia. However, in this study, the dyslipidemia induced by the hypercaloric diet alone, did not promote morphological or functional changes in the thoracic aorta, or insulin resistance evidencing the role of stress in pro-atherogenic effects (Neves et al., 2011).

NPY, a hormone known as orexigenic peptide, may also be involved in the atherogenic effects of stress. Some stressors such as cold and aggression, increase the release of NPY from sympathetic nerves (Kuo et al., 2007). The peripheral actions of NPY are stimulatory, synergizing with glucocorticoids and catecholamines to potentiate the stress response. It causes prolonged vasoconstriction, potentiating the effect of norepinephrine, induces hyperlipidemia, and vascular remodeling via smooth muscle cell proliferation, in addition to stimulating monocyte migration and activation (Kuo et al., 2007). NPY upregulates its Y2 receptors in a glucocorticoid-dependent manner in abdominal fat, consequently leading to abdominal obesity, hyperinsulinemia and dyslipidemia (Kuo et al., 2008). In blood vessels, Y1 and Y5 receptor activation promotes pro-atherogenic responses (Zukowska, 2005).

In addition to all the above-mentioned mechanisms, the inflammatory process also forms part of the stress response (Black, 2003), and is pathophysiologically linked to atherosclerosis (van Oostrom et al., 2004). In the atherogenic process, the high level of catecholamines induced by stress stimulates endothelial permeability to the traffic of oxidized LDL. Once trapped in the endothelium of an artery, LDL can undergo progressive oxidation, cross the endothelial barrier, and be internalized by macrophages expressing scavenger receptors, leading to lipid peroxide formation and accumulation of cholesterol esters, culminating in foam cells formation (Ross, 1999; Singh & Mehta, 2003). Oxidized LDL upregulates the expression of adhesion molecules and secretion of chemokines, which contributes to the recruitment of circulating monocytes and leukocytes (Cersosimo & DeFronzo, 2006; Steinberg, 2002). One of the initial steps in the formation of atherosclerosis is the adhesion of monocytes to the endothelium, their entry into sub-endothelial space, followed by their differentiation into macrophages (Lamharzi et al., 2004). These cells are then responsible for taking up LDL and other particles, thereby starting the atherogenesis process (Lamharzi et al., 2004). In foam cell formation, the macrophages in the endothelial

Dyslipidemia Induced by Stress 375

by arterial wall macrophages (Keidar et al., 1994). Angiotensin II binds LDL and the angiotensin II-modified LDL is taken up by macrophages via scavenger receptors, leading to cellular cholesterol accumulation (Keidar et al., 1996). In atherogenic dyslipidemia, hypercholesterolemia increases AT1R density and its functional responsiveness to vasoconstrictors, whereas the administration of statins reduces AT1R expression and deregulates its functions. Moreover, the localization of angiotensin-converting enzyme in atherosclerotic lesions suggests a capacity for local generation of angiotensin II and proinflammatory substances (Sitia et al., 2010). There is also evidence that hypercholesterolemia increases plasma angiotensinogen and angiotensin peptide production (Sitia et al., 2010), and that AT1R antagonism improves hypercholesterolemia-associated

endothelial dysfunction, resulting in an anti-atherosclerotic effect (Taguchi et al., 2011).

Glucocorticoids

**ATHEROGENESIS**

Fig. 2. Schematic representation of putative mechanisms involved in the relations between among stress, dyslipidemia, and atherosclerosis. Hypothalamic-pituitary-adrenal axis (HPA), neuropeptide Y (NPY), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), free fatty acids (FFA), endothelial nitric oxide synthase (eNOS), nitric oxide (NO), endothelin 1 (ET-1). Solid arrows show stimulatory effects; dashed arrows indicate inhibitory effects.

Endothelial dysfunction

NPY Central Nervous System

Cytokines Monocytes

Oxidized LDL

ET-1

Insulin resistance

HPA axis Sympathetic nervous system

**STRESSOR**

Catecholamines

Dyslipidemia

Oxidative stress

Vascular smooth muscle cells proliferation

eNOS

NO

Adhesion molecules

Peripheral effects via sympathetic nerves

NPY

Monocytes

Abdominal obesity

> FFA + Glucose

Endothelial cells

Leucocytes

Subendothelial

Endothelium

Space

Leucocytes

space also have VLDL receptors, which bind the apolipoprotein (apo) E-containing lipoproteins, including VLDL, intermediate density lipoprotein, and β-migrating VLDL. The LDL-receptor-related protein in macrophages is also capable of binding apo E-containing lipoproteins, lipoprotein lipase, and lipoprotein lipase-triglyceride-rich lipoprotein complex (Nakazato, 1996), leading to a sequence in the development of atherosclerosis.

In addition, high levels of free fatty acids also may amplify monocyte inflammation via tolllike receptors in the presence of high glucose levels (Dasu & Jialal, 2011). Lamharzi et al., 2004, showed that free fatty acids in concert with glucose stimulate machrophage proliferation involving glucose-dependent oxidation of LDL in atherosclerotic lesions. Toll like receptors are expressed by machrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL (Xu et al., 2001). Recently Gu et al., 2009, showed the importance of toll-like receptor 4 in atherosclerosis induced by chronic mild stress in aortas from apolipoprotein-E-knockout-mice. Toll-like receptor 4 is present in T cells, monocytes, and macrophages, and is a key signaling receptor of innate immunity. Toll-like receptor 4 plays an important role in atherogenesis because it recognizes pathogenassociated molecular patterns and activates inflammatory cells via the nuclear factor kB (NF-kB) pathway (Bierhaus et al., 2003; Gu et al., 2009). During the stress reaction, glucocorticoids and catecholamines can induce cytokine production by endothelial cells and macrophages (Black, 2003; Chae et al., 2001) and activation of the NF-kB pathway leads to the synthesis of the following proinflammatory chemokines: interleukin 1-β, inteleukin 6, TNF-α, monocyte chemoattractant protein-1, intercellular adhesion molecule-1. Interleukin 1-β and inteleukin 6 influences smooth muscle cell proliferation and/or migration (Gu et al., 2009), and inhibits eNOS activity (Muniyappa et al., 2008). TNF-α increases endothelin-1 secretion, decreases NO production in endothelial cells, inducing vasoconstriction (Muniyappa & Quon, 2007), and can induce interleukin 6 production (Black, 2003). Monocyte chemoattractant protein-1 is correlated with neointimal proliferation and plays a role in the transition from the stable state of lesion to the more complex state of atherosclerosis (Tellez et al., 2011). Intercellular adhesion molecule-1 may contribute to accelerating atherosclerosis in insulin-resistant states (Muniyappa et al., 2008). Hypertriglyceridemia associated with stress may also increase NF-kB, consequently activating proinflammatory molecules (Fitch et al., 2011).

In addition, the accumulation of macrophages may also be associated with increased plasma concentration of C-reactive protein (CRP) (Ross, 1999). CRP is the principal down-stream mediator of inflammatory acute phase response, which is primarily derived via interleukin 6-dependent hepatic biosynthesis (Pradhan et al., 2001). CRP interacts with oxidized LDL to form proatherogenic oxidized LDL/CRP complexes, perpetuating vascular inflammation, triggering an autoimmune response, and accelerating atherogenesis (Matsuura et al., 2009; Sitia et al., 2010).

Activation of the renin-angiotensin system (RAS) by stress also plays a role in the pathogenesis of endothelial dysfunction, hypertension and atherosclerosis. Lipid accumulation in blood vessels enhances the expression of RAS components, which in turn stimulates accumulation of oxidized LDL in blood vessels (Singh & Mehta, 2003). Activation of the angiotensin II-type 1 receptor (AT1R) leads to vasoconstriction and neurohumoral activation, and is associated with reduced NO bioavailability, vascular cell apoptosis, increased oxidized LDL receptor expression, and proinflammatory cytokine production (Sitia et al., 2010). According Nickening et al., 1999, LDL-cholesterol can accumulate in vascular smooth muscle cells, and this effect is mediated via AT1R. Angiotensin II increases LDL uptake

space also have VLDL receptors, which bind the apolipoprotein (apo) E-containing lipoproteins, including VLDL, intermediate density lipoprotein, and β-migrating VLDL. The LDL-receptor-related protein in macrophages is also capable of binding apo E-containing lipoproteins, lipoprotein lipase, and lipoprotein lipase-triglyceride-rich lipoprotein complex

In addition, high levels of free fatty acids also may amplify monocyte inflammation via tolllike receptors in the presence of high glucose levels (Dasu & Jialal, 2011). Lamharzi et al., 2004, showed that free fatty acids in concert with glucose stimulate machrophage proliferation involving glucose-dependent oxidation of LDL in atherosclerotic lesions. Toll like receptors are expressed by machrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL (Xu et al., 2001). Recently Gu et al., 2009, showed the importance of toll-like receptor 4 in atherosclerosis induced by chronic mild stress in aortas from apolipoprotein-E-knockout-mice. Toll-like receptor 4 is present in T cells, monocytes, and macrophages, and is a key signaling receptor of innate immunity. Toll-like receptor 4 plays an important role in atherogenesis because it recognizes pathogenassociated molecular patterns and activates inflammatory cells via the nuclear factor kB (NF-kB) pathway (Bierhaus et al., 2003; Gu et al., 2009). During the stress reaction, glucocorticoids and catecholamines can induce cytokine production by endothelial cells and macrophages (Black, 2003; Chae et al., 2001) and activation of the NF-kB pathway leads to the synthesis of the following proinflammatory chemokines: interleukin 1-β, inteleukin 6, TNF-α, monocyte chemoattractant protein-1, intercellular adhesion molecule-1. Interleukin 1-β and inteleukin 6 influences smooth muscle cell proliferation and/or migration (Gu et al., 2009), and inhibits eNOS activity (Muniyappa et al., 2008). TNF-α increases endothelin-1 secretion, decreases NO production in endothelial cells, inducing vasoconstriction (Muniyappa & Quon, 2007), and can induce interleukin 6 production (Black, 2003). Monocyte chemoattractant protein-1 is correlated with neointimal proliferation and plays a role in the transition from the stable state of lesion to the more complex state of atherosclerosis (Tellez et al., 2011). Intercellular adhesion molecule-1 may contribute to accelerating atherosclerosis in insulin-resistant states (Muniyappa et al., 2008). Hypertriglyceridemia associated with stress may also increase NF-kB, consequently

In addition, the accumulation of macrophages may also be associated with increased plasma concentration of C-reactive protein (CRP) (Ross, 1999). CRP is the principal down-stream mediator of inflammatory acute phase response, which is primarily derived via interleukin 6-dependent hepatic biosynthesis (Pradhan et al., 2001). CRP interacts with oxidized LDL to form proatherogenic oxidized LDL/CRP complexes, perpetuating vascular inflammation, triggering an autoimmune response, and accelerating atherogenesis (Matsuura et al., 2009;

Activation of the renin-angiotensin system (RAS) by stress also plays a role in the pathogenesis of endothelial dysfunction, hypertension and atherosclerosis. Lipid accumulation in blood vessels enhances the expression of RAS components, which in turn stimulates accumulation of oxidized LDL in blood vessels (Singh & Mehta, 2003). Activation of the angiotensin II-type 1 receptor (AT1R) leads to vasoconstriction and neurohumoral activation, and is associated with reduced NO bioavailability, vascular cell apoptosis, increased oxidized LDL receptor expression, and proinflammatory cytokine production (Sitia et al., 2010). According Nickening et al., 1999, LDL-cholesterol can accumulate in vascular smooth muscle cells, and this effect is mediated via AT1R. Angiotensin II increases LDL uptake

(Nakazato, 1996), leading to a sequence in the development of atherosclerosis.

activating proinflammatory molecules (Fitch et al., 2011).

Sitia et al., 2010).

by arterial wall macrophages (Keidar et al., 1994). Angiotensin II binds LDL and the angiotensin II-modified LDL is taken up by macrophages via scavenger receptors, leading to cellular cholesterol accumulation (Keidar et al., 1996). In atherogenic dyslipidemia, hypercholesterolemia increases AT1R density and its functional responsiveness to vasoconstrictors, whereas the administration of statins reduces AT1R expression and deregulates its functions. Moreover, the localization of angiotensin-converting enzyme in atherosclerotic lesions suggests a capacity for local generation of angiotensin II and proinflammatory substances (Sitia et al., 2010). There is also evidence that hypercholesterolemia increases plasma angiotensinogen and angiotensin peptide production (Sitia et al., 2010), and that AT1R antagonism improves hypercholesterolemia-associated endothelial dysfunction, resulting in an anti-atherosclerotic effect (Taguchi et al., 2011).

Fig. 2. Schematic representation of putative mechanisms involved in the relations between among stress, dyslipidemia, and atherosclerosis. Hypothalamic-pituitary-adrenal axis (HPA), neuropeptide Y (NPY), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), free fatty acids (FFA), endothelial nitric oxide synthase (eNOS), nitric oxide (NO), endothelin 1 (ET-1). Solid arrows show stimulatory effects; dashed arrows indicate inhibitory effects.

Dyslipidemia Induced by Stress 377

condition are at disadvantage, since most of the time they lack the energy and motivation to exercise, and this overwhelming feeling of lethargy seems very difficult to shift (Chaput et al., 2011). In this situation, when psychological stress is not accompanied by physical activity (such as the fight or flight reaction) and by effective use and fast clearance of free fatty acids, triggered by stimulation of the sympathetic nervous system, these are converted into triglycerides by the liver and then circulate in the blood within the VLDL (Howard et al., 1993). In fact, this maladaptative situation can lead to the development of dyslipidemia, reflected by elevated plasma triglyceride and reduced HDL concentration, overproduction of VLDL-apolipoprotein (apo) B-100, decreased catabolism of apoB containing particles, and

While physical inactivity may potentiate the stress-induced allostatic load, there is accumulating evidence suggesting that the adoption of an active lifestyle, including exercise training, may play a protective role in stress system dysregulation, reducing vulnerability to stress, and possibly delaying or preventing the future development of comorbidities, such as dyslipidemia, hypertension and insulin resistance (Roberts & Barnard, 2005; Tsatsoulis & Fountoulakis, 2006). In addition, physical activity may induce favorable changes in traditional and emerging coronary heart disease biomarkers among individuals with, or at high risk of coronary heart disease (Chainani-Wu et al., 2011). Assuming that the stress response is a neuroendocrine mechanism that occurs in anticipation of physical action, it is reasonable to assume that physical activity should provide the vehicle to prevent or combat the somatic and emotional consequences of stress. Thus, physical activity may promote physical and psychological benefits that are involved in both the indirect action of exercise in reducing stress, and a direct effect on various metabolic functions of the body (McMurray

The first rationale for using exercise as a stress reduction strategy was based on the crossstressor adaptation, a promising hypothesis first presented in the 1990s (Sothmann et al., 1996), which has not received strong support since the publication of recent meta-analyses (Forcier et al., 2006; Hamer et al., 2006; Jackson & Dishman, 2006). According to Chaput et al., 2011, the key question now is whether physical activity, which seems to modulate the level of stress, may interact in the relationship between stress and obesity. Different possible mechanisms have been proposed, suggesting that exercise training might protect against stress induced obesity. Regular exercise has been demonstrated to have positive effects on plasma lipid and lipoprotein profiles (Durstine et al., 2002) and these results may have a significant independent effect on HDL cholesterol (Thompson et al., 1988). During physical activity, exercise increases lipid oxidation and lipolysis to ensure an adequate oxygen supply (McMurray & Hanckney, 2005), increases the ability of muscle tissue to take up and oxidize nonesterified fatty acids, and increases muscle lipoprotein lipase activity (Eriksson et al., 1997). Although studies indicate that exercise training changes gene expression in adipose tissue in different ways, affecting some types of adipose tissue more than others (Company et al., 2010), the lowering of plasma triglycerides proves the effects of exercise on VLDL kinetics. Moreover, it is important to highlight that a single 90-min bout of whole body resistance exercise (Tsekouras et al., 2009) or 2h of cycling (Magkos et al., 2006) was proven to be enough to decrease fasting plasma VLDLtriglyceride concentrations by increasing VLDL-triglyceride removal from plasma. These results may be due to the increase in blood flow and hepatic insulin sensitivity associated with

In addition to its possible direct effect modulating the stress response, exercise training improves insulin sensitivity, which might counteract the insulin resistance state produced

increased catabolism of HDL apoA-I particles (Watts et al., 2008; Watts et al., 2009).

& Hanckney, 2005).

an increase in lipoprotein lipase activity.

Atherosclerosis is an inflammatory disease and stress contributes to its development. Therefore, if we can block or minimize the stress components that directly or indirectly induce atherogenesis, it will be possible to preserve the protective components of vascular function and structure, thereby developing new preventive and therapeutic possibilities. Figure 2 illustrates the putative mechanisms of the relations between stress, dyslipidemia, and atherosclerosis.
