Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis
Abstract
Major reactive oxygen species (ROS)–producing systems in vascular wall include NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, xanthine oxidase, the mitochondrial electron transport chain, and uncoupled endothelial nitric oxide (NO) synthase. ROS at moderate concentrations have important signaling roles under physiological conditions. Excessive or sustained ROS production, however, when exceeding the available antioxidant defense systems, leads to oxidative stress. Animal studies have provided compelling evidence demonstrating the roles of vascular oxidative stress and NO in atherosclerosis. All established cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and smoking enhance ROS generation and decrease endothelial NO production. Key molecular events in atherogenesis such as oxidative modification of lipoproteins and phospholipids, endothelial cell activation, and macrophage infiltration/activation are facilitated by vascular oxidative stress and inhibited by endothelial NO. Atherosclerosis develops preferentially in vascular regions with disturbed blood flow (arches, branches, and bifurcations). The fact that these sites are associated with enhanced oxidative stress and reduced endothelial NO production is a further indication for the roles of ROS and NO in atherosclerosis. Therefore, prevention of vascular oxidative stress and improvement of endothelial NO production represent reasonable therapeutic strategies in addition to the treatment of established risk factors (hypercholesterolemia, hypertension, and diabetes mellitus).
Atherosclerosis remains a leading cause of death and disability. The formation of vascular plaques is a complex process involving the interaction of plasma lipids with the vascular wall and immune cells. Since the 1950s, oxidative modifications of lipids and proteins have been detected in vascular lesions and the degree of oxidation correlates with the severity of disease,1 indicating a role of oxidative stress in atherogenesis.
Role of Reactive Oxygen Species–Producing Systems in Atherosclerosis
A variety of important reactive oxygen species (ROS)–producing systems are present in the vascular wall, including NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, xanthine oxidase, enzymes of the mitochondrial respiratory chain, and a dysfunctional, uncoupled endothelial NO synthase.2–4 Importantly, there exists cross talk between these prooxidant systems.5–7 NADPH oxidase can trigger endothelial NOS (eNOS) uncoupling,8 xanthine oxidase activity,9,10 and mitochondrial ROS production.11–14
NADPH Oxidases
NADPH oxidases are expressed not only in infiltrating monocytes/macrophages but also in resident cells of the vascular wall. Consisting of 2 membrane-bound subunits (p22phox and a Nox homologue) and several cytosolic regulatory subunits, these oxidases are multisubunit enzyme complexes and produce superoxide from molecular oxygen using NADPH as the electron donor.15,16 In contrast to Nox1 and Nox2 (that require p22phox, p47phox [or NOXO1], p67phox [or NOXA1] and Rac117), Nox4 only requires p22phox and releases hydrogen peroxide instead of superoxide.18
Three Nox isoforms are expressed in the vascular wall of mice with Nox119 and Nox420 in vascular smooth muscle cells (VSMC), Nox2,21 and Nox422,23 predominantly in endothelial cells. Recent studies have shown that Nox enzymes have differential roles in atherogenesis.24
Genetic deletion of Nox1 in apolipoprotein E-knockout (ApoE-KO) mice reduces atherosclerosis either on an atherogenic diet25 or under the condition of streptozotocin-induced diabetes mellitus26 although some controversies exist.27 Nox1 may be especially important in diabetes mellitus–accelerated atherosclerosis as diabetic conditions lead to upregulation of this Nox isoform.26,28 Nox2 is also implicated in atherogenesis29 with some regional differences. Nox2 deficiency has no effect on atherosclerosis in the aortic sinus, but reduce atherosclerosis in the descending aorta of mice.30,31 Consistent with the atherogenic roles of Nox1 and Nox2, deficiency of p47phx, a regulatory subunit required for the activation of the both Nox isoforms, reduces atherosclerosis in mice32,33 (Table 1).
| Gene Altered | Genetic Background | Diet/Intervention | Atherosclerosis | References |
|---|---|---|---|---|
| Nox1-/y | ApoE-KO | Atherogenic diet | ↓ | 25 |
| Nox1-/y | ApoE-KO | Normal chow/diabetes mellitus | ↓ | 26 |
| Nox1-/y | ApoE-KO | Western diet | ↔ | 27 |
| Nox2-/y | ApoE-KO | Atherogenic diet | ↔ | 30 |
| Nox2-/y | ApoE-KO | Western diet | ↓ | 31 |
| Endothelial Nox2 Tg | ApoE-KO | Normal chow±angiotensin II | ↔ | 34 |
| p47phox−/− | ApoE-KO | Normal chow | ↔ | 32 |
| p47phox−/− | ApoE-KO | Normal chow | ↓ | 33 |
| p47phox−/− | ApoE-KO | High fat | ↓ | 33 |
| Endothelial-Nox4 Tg | ApoE-KO | Western diet | ↔ (12 w)↓ (24 w) | 35 |
| Nox4−/− | ApoE-KO | Normal chow or high-fat diet | ↑ | 36 |
| Nox4−/− | LDL-R-KO | High-fat diet | ↑ | 37 |
| Nox4−/− | ApoE-KO | Normal chow/diabetes mellitus | ↑ | 28 |
In contrast to the proatherosclerotic role of Nox1 and Nox2, several groups have independently shown that Nox4 protects against atherosclerosis in murine models28,35–37 (Table 1). The protective role of Nox4 against atherosclerosis may be explained by the following facts: (1) Nox4 releases hydrogen peroxide instead of superoxide because of spontaneous superoxide dismutation within the Nox4 enzyme.38 (2) Nox4 does not lead to peroxynitrite generation because the Nox4 product hydrogen peroxide does not interact with NO.24,38 (3) Hydrogen peroxide produced by Nox4 maintains eNOS and heme oxygenase-1 expression in the setting of vascular stress.18,39 (4) Nox4-derived hydrogen peroxide inhibits proliferation of vascular smooth muscle cells40 and prevents vascular inflammation and remodeling.28 Nevertheless, Nox4 is not universally beneficial. Detrimental roles of Nox4 have been shown in rodent models of ischemic stroke,41,42 cardiac hypertrophy,43 and diabetic cardiomyopathy.44 Like other ROS, hydrogen peroxide may have both protective and damaging functions, depending on the amounts formed, the cell type expressing the Nox enzyme and its subcellular location.
Nox5 has been found upregulated in human atherosclerotic lesions,45 in human hypertension46 and in human diabetic nephropathy.47 The rodent genome does not contain the Nox5 gene, making it challenging to study Nox5 in experimental settings. Interestingly, transgenic mice expressing human Nox5 in a podocyte-specific manner exhibit early onset albuminuria and elevated systolic blood pressure, suggesting a role for Nox5 in disease processes.47 Nevertheless, the impact of Nox5 on atherosclerosis development remains elusive.24,48
It is notable that Nox enzymes in both monocytes/macrophages and cells of the vascular wall are required for atherogenesis. Results from bone marrow transplantation experiments using ApoE-KO and p47phox−/− mice indicate that NADPH oxidase activity in monocytes/macrophages is essential for low-density lipoprotein (LDL) oxidation. ROS produced by NADPH oxidases in endothelial cells and smooth muscle cells, on the other hand, are involved in endothelial activation (expression of adhesion molecules and the subsequent monocyte/macrophage infiltration) and smooth muscle cell proliferation.49 Consistent with this concept, endothelial-specific Nox2 overexpression increases vascular superoxide production, endothelial vascular cell adhesion molecule-1 expression, and macrophage recruitment, but does not induce atherosclerosis in ApoE-KO mice.34
Xanthine Oxidase
Xanthine oxidase (XO) generates superoxide and hydrogen peroxide by using molecular oxygen as an electron acceptor.50,51 The expression and activity of endothelial XO are enhanced by proatherosclerotic stimuli such as angiotensin II treatment10 and oscillatory shear stress.9 In addition, XO can be released from the liver and the circulation XO adhere to endothelial cells by associating with endothelial glycosaminoglycans.52 The activity of both endothelial XO53 and plasma XO52 is increased in experimental atherosclerosis, as well as in human atherosclerotic plaque,54,55 suggesting a contribution of XO-derived superoxide to atherosclerosis. Inhibition of XO improves endothelium-dependent, NO-mediated vasodilation in aorta rings from hypercholesterolemic animals52 and reverses endothelial dysfunction in heavy smokers.56 XO inhibitors, such as allopurinol, tungsten,57 and febuxostat,51 reduce atherosclerosis development in ApoE-KO mice. However, definitive proof of its role in atherosclerosis remains to be established, as no data from genetically modified murine models are available.
Mitochondria
Normally, mitochondrial oxidative phosphorylation generates physiological levels of superoxide, which is converted to hydrogen peroxide by the manganese-dependent superoxide dismutase (MnSOD, SOD2) and subsequently by glutathione peroxidase 1 (GPx1) to water.58 Mitochondrial oxidative stress can occur under pathological conditions because of excessive ROS production or insufficient ROS detoxification. Indeed, atherosclerosis in human has been associated with mitochondrial oxidative stress.59
The importance of mitochondrial redox balance is exemplified by a global or cardiac deletion of mitochondrial SOD2, which causes perinatal lethality because of cardiac myopathy and congestive heart failure, respectively.60,61 Heterozygous SOD2+/− knockout mice on ApoE-KO background show increased ROS levels in the mitochondria and accelerated atherogenesis at arterial branch points.62
Uncoupled eNOS
Under physiological conditions, eNOS produces NO, which represents a key vasoprotective factor of the endothelium.63–65 Under pathological conditions associated with oxidative stress, however, eNOS may become dysfunctional.2,66,67 Oxidative stress contributes to endothelial dysfunction primarily because of rapid oxidative inactivation of NO by excess superoxide. In the second step, the persisting oxidative stress renders eNOS uncoupled (ie, uncoupling of O2 reduction from NO synthesis), such that it produces superoxide at the expense of NO. Mechanistically, deficiency of eNOS cofactor tetrahydrobiopterin (BH4), deficiency of eNOS substrate l-arginine, and eNOS S-glutathionylation are likely to be the major causes for eNOS uncoupling.66,68 Peroxynitrite and superoxide can oxidize BH4 leading to BH4 deficiency. ROS production from uncoupled eNOS has been shown in mouse models of atherosclerosis69–71 and in patients with hypercholesterolemia,72 atherosclerosis,73 hypertension74 or diabetes mellitus,75 and in chronic smokers.76
Cyclooxygenases
Although there is evidence that cyclooxygenases may indirectly modulate vascular ROS generation,77 it is unlikely that the cyclooxygenase enzymes per se serve as sources of pathogenic ROS.78 Cyclooxygenase-1 inhibition or deletion in fact attenuates atherogenesis in mice.79,80 Experiments with cell-specific deletion of cyclooxygenase-2 in mice indicate a complex role of cyclooxygenase-2 in atherogenesis. Whereas cyclooxygenase-2 in macrophages promotes atherosclerosis development, cyclooxygenase-2 in T cells has little effect on lesion burden.81 In contrast, cyclooxygenase-2 in endothelial cells and VSMC seems to be atheroprotective.82 The beneficial effects of cyclooxygenase-2 have been attributed to prostacyclin biosynthesis,82 but prostacyclin-independent mechanisms have also been proposed.83
Role of Antioxidant Enzymes in Atherosclerosis
Vascular cells are equipped with a variety of antioxidant defense enzymes enabling the reduction of oxidative burden.
Superoxide Dismutase
There are 3 SOD isoforms expressed in mammalian tissues: (1) SOD1 (copper/zinc-SOD), which is located in the cytoplasm and in the mitochondrial intermembrane space; (2) SOD2, which is expressed in the mitochondrial matrix, and (3) SOD3 (extracellular SOD), which is found in extracellular matrix, on cell surface, and in extracellular fluids.84,85 All 3 isozymes serve key antioxidant functions by catalyzing the dismutation of superoxide into oxygen and hydrogen peroxide.4,65
Unexpectedly, transgenic mice overexpressing SOD1 develop more pronounced atherosclerotic lesion than control mice.86 It is proposed that the effects of SOD on atherogenesis are dose dependent.87 Moderate SOD1 upregulation reduces ROS burden, whereas excessive SOD activity could enhance oxidative injury by increasing formation of distal oxidants. SOD1 overexpression generates high amount of hydrogen peroxide, which can lead to the formation proatherogenic molecules such as hydroxyl radicals or metal-associated reactive species85 (Figure 1). In supporting this concept, combined overexpression of SOD1 and catalase reduces atherosclerosis in ApoE-KO mice.88
Figure 1. Enzymes involved in the generation and inactivation of reactive oxygen species (ROS). Superoxide anion (O2·-) can be produced in the vascular wall by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidases (Nox1 and Nox2), xanthine oxidase, uncoupled endothelial nitric oxide synthase (eNOS), and the mitochondrial respiration chain. O2·- can be converted to hydrogen peroxide (H2O2) by the enzyme superoxide dismutase (SOD). H2O2 can undergo spontaneous conversion to hydroxyl radical (OH·) via the Fenton reaction. OH· is extremely reactive and attacks most cellular components. H2O2 can be detoxified via glutathione (GSH) peroxidase, catalase or thioredoxin (Trx) peroxidase to H2O and O2. The enzyme myeloperoxidase can use H2O2 to oxidize chloride to the strong-oxidizing agent hypochlorous acid (HOCl). HOCl can chlorinate and thereby inactivate various biomolecules including lipoproteins and the eNOS substrate l-arginine. Besides HOCl generation, myelo-peroxidase can oxidize (and thus inactivate) NO to nitrite (NO2−) in the vasculature. Paraoxonase (PON) isoforms 2 and 3 can prevent mitochondrial O2·- generation. Reprinted from Li et al67 with permission of the publisher. Copyright © 2013, Elsevier.
SOD2 is the first line of defense against superoxide as a byproduct of the mitochondrial electron transport chain. Homozygous SOD2 mutant mice die within the first 10 days of life, indicating the importance of this enzyme.60 SOD2 deficiency (SOD2+/−) leads to mitochondrial dysfunction, increased mitochondrial DNA damage, and accelerated atherosclerosis in ApoE-KO mice.62
SOD3 is abundantly expressed in the vascular wall.89 Paradoxically, genetic deletion of SOD3 in ApoE-KO mice leads to a slight reduction in atherosclerosis after 1-month atherogenic diet, whereas no effect can be found after 3 months on the atherogenic diet or after 8 months on standard chow.90 Therefore, functional significance of SOD3 in atherogenesis is still unclear and warrants more studies in future.
Overall, the effect of SOD enzymes on atherosclerosis is likely to be context dependent. SOD enzymes may have antiatherosclerotic effects by inhibition of oxidative damages caused by superoxide and by prevention of superoxide-mediated inactivation of NO. However, SOD may also enhance oxidative stress in case that the capacity of downstream enzymes (eg, catalase and GPx) is insufficient to detoxify SOD the product (Table 2).
| Enzyme | Gene Altered | Genetic Background | Diet/intervention | Atherosclerosis | References |
|---|---|---|---|---|---|
| SOD1 | SOD1 Tg | B6 | Atherogenic diet | ↑ | 86 |
| SOD1 Tg | B6 | Atherogenic diet+irradiation | ↓ | 91 | |
| SOD1 Tg | ApoE-KO | Normal chow | ↔ | 88 | |
| SOD1 Tg+CAT Tg | ApoE-KO | Normal chow | ↓ | 88 | |
| SOD1 Tg | ApoE-KO | Normal chow+BaP | ↓ | 92 | |
| SOD1 Tg+CAT Tg | ApoE-KO | Normal chow+BaP | ↓↓ | 92 | |
| SOD2 | SOD2+/− | ApoE-KO | Normal chow | ↑ | 62 |
| SOD3 | SOD3−/− | ApoE-KO | Normal chow | ↓ (1 mo)↔ (3 mo) | 90 |
| SOD3−/− | ApoE-KO | Atherogenic diet | ↔ (8 mo) | 90 | |
| Catalase | CAT Tg | ApoE-KO | Normal chow | ↓ | 88 |
| CAT Tg | ApoE-KO | Normal chow+BaP | ↓ | 92 | |
| GPx1 | GPx1−/− | B6 | High fat | ↔ (12 wk)↓ (20 wk) | 93 |
| GPx1−/− | ApoE-KO | Western diet | ↑ | 94 | |
| GPx1−/− | ApoE-KO | Normal chow+streptozotocin | ↑ | 95 | |
| GPx4 | GPx4 Tg | ApoE-KO | Normal chow | ↓ | 96 |
| PON1 | PON1 Tg | B6 | Atherogenic diet | ↓ | 97 |
| PON1 Tg | ApoE-KO | Normal chow | ↓ | 97 | |
| PON1−/− | B6 | Atherogenic diet | ↑ | 98 | |
| PON2 | PON2 Tg | ApoE-KO | Normal chow | ↓ | 99 |
| PON2−/− | B6 | Atherogenic diet | ↑ | 100 | |
| PON3 | PON3 Tg | B6 | Atherogenic diet | ↓ | 101 |
| PON3 Tg | LDLR-KO | Western diet | ↓ | 101 | |
| Thioredoxin-2 | Endothelial Tg | ApoE-KO | Western diet | ↓ | 102 |
Catalase
Catalase is located exclusively in peroxisomes58 where it catalyzes the reduction of hydrogen peroxide to oxygen and water. Overexpression of catalase reduces atherosclerosis in ApoE-KO mice.88
Although ROS indisputably participate in atherogenesis, it is likely that the relative contribution of different ROS varies in different atherosclerosis models (Table 2). This becomes apparent when SOD1 is compared with catalase in mouse atherosclerosis models. In ApoE-KO mice on high-fat diet, overexpression of catalase reduces atherosclerosis, whereas SOD1 overexpression is ineffective.88,92 It is likely that superoxide makes only a minor contribution to the atherosclerosis induced by a high-fat diet or by ApoE deficiency. It has been suggested that these atherogenic stimuli (eg, oxidized low-density lipoprotein [oxLDL]) lead to the accumulation of peroxides and not superoxide.103 In contrast, the effect of SOD1 overexpression is evident in atherosclerosis models where both hydrogen peroxide and superoxide participate in atherogenesis, such as x-ray exposure91 or treatment with the environmental pollutant benzo(a)pyrene.92
Glutathione Peroxidases
By reducing hydrogen peroxide to water and lipid hydroperoxides to their corresponding alcohols, glutathione peroxidases (GPx) represent the major antioxidant enzyme within many cells.104 GPx1 is the ubiquitous intracellular member of the GPx family and is expressed both in the mitochondria and in the cytoplasm. A low activity of red blood cell GPx1 is associated with an increased risk of cardiovascular events in patients with coronary artery disease (CAD).105 GPx1 deficiency increases LDL oxidation, foam cell formation, and macrophage proliferation.106 Two independent studies have shown that deficiency of GPx1 enhances atherosclerosis in ApoE-KO mice,94,95 indicating a protective role of GPx1 against atherogenesis. Consistently, seleno-organic GPx1-mimetics also reduce atherosclerotic lesions in diabetic ApoE-KO mice.107
Similar antiatherosclerotic properties have been shown for GPx4, although this GPx enzyme differs significantly from the other GPx family members in structure, intracellular localization, and functional characteristics.108 GPx4 reduces hydrogen peroxide and a wide range of lipid hydroperoxides, including oxidized phospholipids and cholesterol hydroperoxides.96 GPx4 overexpression reduces atherosclerosis in ApoE-KO mice by preventing lipid peroxidation and oxidized lipid sensing by vascular cells.96
Paraoxonases
The paraoxonase family of proteins has 3 members (paraoxonase 1, paraoxonase 2, and paraoxonase 3) with overlapping and discrete esterase and lactonase activities, metabolizing/hydrolyzing arachidonic acid oxidation products (all 3 paraoxonases), organophosphates (paraoxonase 1), quorum-sensing signals of pathogenic bacteria (N-acyl-homoserine lactones by paraoxonase 2), and drugs (eg, lovastatin and spironolactone by paraoxonase 3).109 All 3 paraoxonase proteins reduce oxidative stress, decrease lipid peroxidation, and diminish atherosclerosis, but with different mechanisms.
Paraoxonase 1 is mainly synthesized by the liver and associates with high-density lipoprotein (HDL) particles. Many of the antiatherosclerotic properties of HDL are partly attributed to the esterase, peroxidase-like, and phospholipase-like activities of paraoxonase 1.110–112 HDL-associated paraoxonase 1 inhibits the formation of oxidized phospholipids and thus LDL oxidation. Overexpression of paraoxonase 197,113 reduces atherosclerosis, whereas disruption of paraoxonase 1 gene98 exacerbates atherogenesis (Table 2).
Paraoxonase 2 is undetectable in plasma114 but abundantly expressed in the vascular wall. Paraoxonase 2 is found in intracellular structures, such as the membranes of the ER or mitochondria, where it reduces superoxide formation and ER stress signaling.115,116 Interestingly, paraoxonase 2 can translocate to the plasma membrane in response to oxidative stress where it suppresses lipid peroxidation and regulates glucosylceramide content.117 Paraoxonase 2 prevents LDL peroxidation, reduces oxidative stress in all major vascular cells,100,116 and protects against atherosclerosis in mouse models (Table 2).99,100 In humans, paraoxonase 2 expression is found decreased in plaques versus plaque-adjacent tissue, indicating that the protective effect of paraoxonase 2 could fail during atherosclerosis development.118
Paraoxonase 3 is found both in serum and cells and prevents LDL oxidation like paraoxonase 1.119 Similar to paraoxonase 2, paraoxonase 3’s antioxidative effect results from the prevention of mitochondrial superoxide formation because of an interaction with coenzyme Q10 (ubiquinone).115,120 During the Q cycle, the unstable intermediate ubisemiquinone can donate an electron to molecular oxygen leading to superoxide production. Paraoxonase 2 and paraoxonase 3 are present in the inner mitochondrial membrane and bind to coenzyme Q10 with high affinity. The 2 paraoxonase enzymes sequester ubisemiquinone and thereby reduce mitochondrial superoxide formation.115,120,121 Paraoxonase 3 counteracts atherosclerosis in mice,101 and its expression level is reduced in vascular cells of atherosclerotic patients.122
Thioredoxins
The thioredoxin systems involve thioredoxin, thioredoxin reductases, and thioredoxin peroxidases.123,124 Thioredoxin can reduce target proteins via cysteine thiol-disulfide exchanges. Thioredoxin-dependent peroxidase can also directly scavenge hydrogen peroxide, and thioredoxin reductase converts oxidized thioredoxin to its reduced form to facilitate its redox activity (Figure 1). Experiments with transgenic mice have shown that both the cytosolic thioredoxin-1 and the mitochondrial thioredoxin-2 systems are essential regulators of cardiac function.123,124 For the vascular system, compelling evidence exists supporting a crucial role of the thioredoxin-2 system. Endothelial-specific deletion of thioredoxin-R2 leads to increased vascular stiffness, impaired endothelial function, and a prothrombotic, proinflammatory vascular phenotype.125 Endothelial-specific overexpression of mitochondrial thioredoxin-2 improves endothelial function and reduces atherosclerotic lesions in ApoE-KO mice.102
Role of NO in Atherosclerosis
Results from studies using genetically modified animals indicate that NO synthase (NOS) isoforms have different roles in atherosclerosis with eNOS and neuronal nitric oxide synthase (nNOS) being atheroprotective and inducible nitric oxide synthase (iNOS) being proatherogenic.126
Neuronal NO Synthase
The nNOS is expressed in not only perivascular nerve fibers but also the vascular wall127,128 and atherosclerotic plaques.129 Vascular nNOS contributes to vasodilation130 and can partly compensate the loss of eNOS in eNOS−/− mice.131–133 Recent human studies suggest that nNOS plays an important role in the local regulation of vascular tone independently of its effect in the central nervous system. Inhibition of nNOS reduces the basal blood flow in human forearm and coronary circulations without affecting the eNOS-mediated vasodilatation elicited by acetylcholine, substance P, or increased shear stress,134,135 indicating distinct roles of nNOS and eNOS.
Disruption of nNOS gene enhances neointimal formation and constrictive vascular remodeling in a mouse model of carotid artery ligation.128,136 Double knockout (DKO) mice deficient in nNOS and ApoE show markedly larger atherosclerotic lesion in the aortic root and descending thoracic aorta129,137 and increased mortality137 (Table 3).
| Enzyme | Gene Altered | Genetic Background | Diet/intervention | Atherosclerosis | References |
|---|---|---|---|---|---|
| nNOS | nNOS−/− | ApoE-KO | Western diet | ↑ | 137 |
| iNOS | iNOS−/− | ApoE-KO | Western diet | ↓ | 138 |
| eNOS | eNOS−/− | ApoE-KO | Western diet | ↑ | 139–141 |
| eNOS-Tg | ApoE-KO | Western diet | ↑ | 142 | |
| eNOS-Tg xGCH1-Tg | ApoE-KO | Normal chow | ↓ (vs eNOS-Tg)↔ (vs ApoE-KO) | 143 |
Inducible NO Synthase
The inducible isoform iNOS is normally absent in the vasculature under physiological conditions. Its expression is induced in blood vessels in pathological situations, such as inflammation, sepsis, or oxidative stress.144
Genetic disruption of iNOS ameliorates atherosclerotic lesion in ApoE-KO mice without changing the lipid profile138 (Table 3). The reduced atherosclerosis in iNOS/ApoE DKO mice is associated with decreased plasma levels of lipoperoxides, indicating that peroxynitrite-mediated oxidative stress is likely to be involved in the proatherosclerotic effects of iNOS.138
In contrast to the regulated production of NO by nNOS and eNOS, iNOS may generate large amounts of NO over long periods of time. If induced in endothelial cells, iNOS competes with eNOS for BH4 and thus reduces eNOS-mediated NO production by limiting BH4 availability for eNOS.145 Furthermore, iNOS induction in the vasculature facilitates the generation of peroxynitrite,146–149 a key proatherosclerosis oxidant.150,151 Indeed, the expression of iNOS in human atherosclerosis plaque is associated with nitrotyrosine, a marker of peroxynitrite formation.149,152,153
Endothelial NO Synthase
The eNOS enzyme is constitutively expressed mainly in endothelial cells. Its activity is regulated by shear stress of the flowing blood and by agonists such as bradykinin and acetylcholine. Endothelial NO produced by eNOS induces vascular smooth muscle relaxation and inhibits platelet aggregation and adhesion.63–65 In addition to these antihypertensive and antithrombotic properties, eNOS-derived NO also exerts multiple antiatherosclerotic effects, including inhibition of LDL oxidation, prevention of leukocyte adhesion to vascular endothelium and leukocyte migration into the vascular wall, and inhibition of vascular smooth muscle cell proliferation.63–65 At low physiological levels, NO also acts as an antioxidant, abating fenton-type reactions, terminating radical chain reactions, and inhibiting peroxidases and oxidases (eg, by nitrosylation of allosteric thiols).154
Consistent with the antiatherosclerotic role of eNOS-derived NO, genetic disruption of eNOS in ApoE-KO mice enhances atherosclerosis139,140 (Table 3). Unexpectedly, overexpression of eNOS also accelerates atherogenesis in ApoE-KO mice.142 This paradoxical phenomenon is explained by later findings that eNOS overexpression leads to eNOS uncoupling owing to a relative deficiency of eNOS cofactor BH4. Indeed, reversal of eNOS uncoupling by upregulating BH4 synthesis in ApoE-KO/eNOS-Tg mice leads to a reduction of atherosclerotic lesion.143
The eNOS-KO mice are hypertensive. However, hypertension does not account for the accelerated atherosclerosis in the eNOS-KO animals. Treatment of ApoE/eNOS DKO mice with hydralazine lowers the blood pressure to levels seen in ApoE-KO mice, but does not change the extent of lesion formation in ApoE/eNOS-DKO mice. These results indicate that hypertension is not required for the accelerated atherosclerosis seen in apoE/eNOS DKO animals and that eNOS plays important roles in suppressing atherogenesis separate from blood pressure regulation.140
Recent studies have shown that eNOS is also present in the perivascular adipose tissue. Under physiological conditions, NO derived from perivascular adipose tissue–eNOS contributes to the vasoprotective effects of perivascular adipose tissue. Under pathological conditions, however, perivascular adipose tissue–eNOS may become a superoxide-generating enzyme.155,156
Differences Between Murine Models and Human Pathology
Although the ApoE-KO and the LDL receptor-KO mice are excellent models for atherosclerosis research, there exist significant differences between these commonly used murine models and human pathology.157,158 For instance, (1) these mice have usually excessive blood cholesterol levels; they are not common in human patients. (2) The majority of lipoproteins are found in the HDL fraction in mice, whereas it is in LDL and very-low-density lipoprotein in humans. (3) Murine atherosclerosis studies are mostly performed in relatively young mice without aging. (4) There are significant differences between the murine and human immune systems. (5) Mice do not develop plaque rupture on a regular basis.157,158 Therefore, these differences must be considered when translating results from murine experiments into clinical settings.
Because of the significance of such differences, mouse models for plaque rupture have been developed. The brachiocephalic artery in ApoE-deficient mice fed a high-fat diet, with or without angiotensin II infusion, is a practically feasible model for plaque rupture.159 It has been shown in this model that monocyte/macrophage-mediated oxidative stress and inflammation are likely to be involved in plaque destabilization and plaque rupture.160 Recently, a mouse model with a fibrillin-1 gene mutation on the ApoE-KO background has been described as a model of acute plaque rupture with human-like complications.161 Also in this model, lipid oxidation and iNOS-mediated inflammation are likely to play roles in the pathology.
In both the ApoE-KO and LDL receptor-KO mice, atherogenesis is driven, at least in part, by non-HDL hyperlipidemia, although the underlying mechanisms are different.162 Because ApoE has antioxidative properties, the oxidation of lipoproteins is more prominent in apoE-KO mice than in LDL receptor-KO mice. Consistently, antibodies to oxidized LDL epitopes are especially high in the ApoE-KO mice.162 There are no data available directly comparing the levels of endothelial NO between the 2 mouse models.
There exist sex differences in atherosclerosis,163 both in humans164 and mice.165 Atherosclerotic lesion formation and lipid accumulation in the aorta from ApoE-KO mice is more pronounced in men than women.165 These sex-dependent differences are associated with lower NADPH oxidase activity in the women.165 Moreover, ovariectomy enhances NADPH oxidase activity, lipid deposition, and atherosclerotic lesion formation, which can be recovered by administration of 17β-estradiol, indicating the role of female sex hormones.165,166 Furthermore, arteries from female animals also show higher expression of SOD1, SOD2, and eNOS.167 Estrogens have been shown to enhance eNOS expression and NO production in endothelial cells.168
Gene Polymorphisms and Atherosclerosis in Humans
Genome-wide association studies have identified 58 single-nucleotide polymorphisms that are genome-wide significantly associated with CAD.169,170 Ten of the CAD loci are associated with LDL and another 5 with blood pressure,170 which should not be surprising. On the contrary, the majority of the CAD genome-wide association study loci is not associated with known risk factors for CAD.170 The redox genes and NO synthase genes mentioned in this article are not among the 58 CAD genome-wide association study loci, either.
In contrast to genome-wide association studies, hypothesis-driven candidate gene association studies have provided evidence for possible association of redox gene and eNOS gene polymorphisms with the risk of atherosclerosis (Table 4). Unfortunately, the results are often conflicting and inconclusive, partially because of the small sample size in each study or the differences in ethnicity.
| Enzyme | rs Number | Polymorphism | Functional Consequence | Effects on Atherosclerosis |
|---|---|---|---|---|
| Nox2 | rs4673 | C242T (His72Tyr) | Nox2 activity↓ | CAD ↓171–173 |
| CAD ↑174,175 | ||||
| SOD1 | rs9974610 | A→G (≈13.6 kb 5' from TSS) | Unknown | CV death risk ↓176 |
| rs10432782 | T→G (intron 2) | Unknown | CV death risk ↑176 | |
| rs1041740 | C→T (intron 4) | Unknown | ||
| SOD2 | rs4880 | Ala16Val | ↓SOD2 into mitochondria | CAD ↑177–179 |
| SOD3 | rs1799895 | Arg213Gly | ↓SOD3 tissue binding | CAD risk ↑180,181 |
| GPx1 | rs1050450 | Pro198Leu | GPx1 activity↓ | IMT ↑182; CAD ↑183,184 |
| GPx1 activity ↔ | No effect185,186 | |||
| eNOS | rs1799983 | Glu298Asp | eNOS activity↓ | CAD ↑187–189 |
| rs 2070744 | -T786C | eNOS expression↓ | CAD ↑189,190 | |
| Intron 4 VNTR | eNOS expression↓? | CAD ↑187,189 |
NADPH Oxidase Subunits
The p22phox subunit is required by Nox family members of NADPH oxidases. The Nox proteins and the p22phox protein are stable only as a heterodimer. A significant number of allelic variants have been identified within the promoter and exonic sequences of the p22phox gene.191 Among these, particular attention has been paid to the C242T polymorphism which results in replacement of histidine by tyrosine at amino acid position 72 (H72Y), a potential heme binding site.174 The 242T allele has been shown to be associated with reduced NADPH oxidase activity and respiratory burst in human neutrophils,192 and with decreased vascular NADPH oxidase activity in saphenous veins of patients with CAD, independently of other clinical risk factors.193 Although some studies indicate that the T allele may confer protection against atherosclerosis,171–173 some other studies have shown negative or even opposite effects.174,175 Two recent meta-analyses have also provided conflicting results.194,195 Therefore, more studies are needed before a definitive conclusion can be drawn.
Whereas the C242T variant is a rather common (T allele ≈20%194) genetic polymorphism, the chronic granulomatous disease is a rare (1 in 200 000–250 000 individuals) inherited disorder of the innate immune system and caused by genetic defects in the genes encoding 4 of the phox proteins (Nox2/gp91phox, p22phox, p47phox, and p67phox).191 The deficiency of Nox2 activity in patients with chronic granulomatous disease results in an improved flow-mediated arterial dilation196 and a protection of the vascular endothelium against ischemia/reperfusion-induced endothelial dysfunction in the brachial artery.197 Moreover, individuals with chronic granulomatous disease have lower carotid intimal-medial thickness198 and reduced carotid atherosclerosis,199 although coronary atherosclerosis is not changed by chronic granulomatous disease.199 All these observations support the concept that Nox2 activity contributes to atherogenesis in humans. Consistently, upregulation of Nox2 is evident in coronary arteries of human patients with atherosclerosis55,200
SOD Enzymes
Association studies for SOD1 has been scarce. A recent study has found that 3 variants in the SOD gene are associated with increased risk of death from cardiovascular causes (sudden death, fatal myocardial infarction, or stroke).176
A functional polymorphism has been identified in the SOD2 gene resulting in the replacement of alanine 16 with a valine (Ala16Val) in the mitochondrial targeting domain. Human beings harboring this variant have an increased carotid intima-to-media thickness and are at increased risk for CAD and acute myocardial infarction.177–179
Genetic variants exist in both the coding region and the promoter region of SOD3 gene.201 Most researches have concentrated on the functional variant Arg213Gly in the heparin-binding domain. The Gly allele is associated with decreased SOD3 affinity for heparin, reduced tissue binding,202–204 and reduced antioxidant effects in the vascular wall.204 This polymorphism has been linked to increased body weight, triglycerides, and higher cardiovascular risk180,181 but paradoxically decreased risk of lung disease.205
GPx1
The Pro198Leu polymorphism is a site located within the GPx1 C-terminal region. This amino acid substitution has been proposed to change structural conformation of the active site region and to modify the enzyme activity.206 GPx1 polymorphism has been associated with increased carotid intima-to-media thickness, peripheral arterial disease, and increased CAD risk.182–184,207 However, other studies found no association of Pro198Leu polymorphism with stroke208 or coronary artery stenosis.185,186 The predicted tertiary structure of GPx1 shows that the C-terminal fragment containing the Pro198Leu polymorphic site is located on the protein surface and within a nonfunctional fragment.185
eNOS
The most intensively examined and functionally related common eNOS variants include Glu298Asp (G894T), -T786C, and the intron 4 variable number tandem repeat.187,209 Early studies suggested that eNOS protein containing 298Asp is subject to selective proteolytic cleavage.210,211 These observations, however, turned out to be artifacts.212,213 A later study has provided evidence that the Glu298Asp single-nucleotide polymorphism affects eNOS localization to caveolar membrane leading to diminished shear-dependent responses and impaired coordination of the eNOS regulatory cycle.214 A large number of genetic association studies exist addressing the impact of Glu298Asp polymorphisms on atherosclerosis risk with partly promising results.188,215–217 However, negative findings have also been reported.184,218,219 Results from several meta-analyses indicate positive associations of Glu298Asp,187–189 -786T>C,189,190 and Intron 4189 polymorphisms with CAD risk.
Cardiovascular Risk Factors Induce Vascular Oxidative Stress and Decrease Endothelial NO Production
All established risk factors for atherosclerosis enhance oxidative stress and induces eNOS uncoupling in the vascular wall.66,67 Uncoupling of eNOS leads to not only reduced endothelial NO production but also a potentiation of oxidative stress (Figure 2).
Figure 2. Cardiovascular risk factors induce vascular oxidative stress and reduce endothelial nitric oxide (NO) production. Hypercholesterolemia, hypertension, smoking, and diabetes mellitus lead to activation of NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, partly through mechanism dependent on protein kinase C (PKC). Diabetes mellitus also stimulates mitochondrial ROS production, which then triggers NADPH oxidase activation. NADPH oxidase can enhance superoxide (O2·-) production from mitochondria and xanthine oxidase. The endothelial NO synthase (eNOS) enzyme can become uncoupled through 2 major mechanisms: deficiency of the cofactor tetrahydrobiopterin (BH4) or of the substrate l-arginine. O2·- reacts with NO resulting in peroxynitrite (ONOO-). ONOO- oxidizes BH4 leading to BH4 deficiency. l-Arginine deficiency is caused by upregulation of arginase expression and activity, partly through RhoA/ROCK-dependent mechanisms. Uncoupled eNOS produces superoxide thereby potentiating oxidative stress. The uncoupling of eNOS decreases endothelial NO production, which is further exacerbated by reduced eNOS expression and activity. In addition to the risk factors at the population level, disturbed flow renders arterial bifurcations and side branches prone to atherosclerosis. Enhanced oxidative stress and reduced endothelial NO production contribute significantly to the enhanced atherosclerosis at these regions.
Hypertension
Hypertension is a major risk factor for atherosclerosis and for CAD and stroke. One of the underlying mechanisms for the enhanced atherogenesis in hypertension patients is oxidative stress. In fact, oxidative stress plays a crucial role in the pathogenesis of hypertension itself. This has been shown for variety animal models of hypertension types, including angiotensin II–induced hypertension, spontaneously hypertensive rats (an animal model of genetic hypertension), and deoxycorticosterone acetate-salt hypertension, which is a low renin/angiotensin hypertension model. Moreover, NADPH oxidase is likely to represent the primary ROS source. Genetic deletion or pharmacological inhibition of NADPH oxidase lowers blood pressure in hypertension models.8,220,221
Uncoupled eNOS also contributes significantly to vascular oxidative stress in hypertension.66,67 Molecular mechanisms for eNOS uncoupling in hypertension include BH4 deficiency, l-arginine deficiency, and S-glutathionylation. The deficiency of BH4 is caused by NADPH oxidase–mediated of BH4 oxidation8 and by reduced BH4 recycling from BH2 because of a downregulation of endothelial dihydrofolate reductase.222l-Arginine deficiency in hypertension models has been attributed to upregulation of arginase expression/activity in blood vessels.223–225 Uncoupling of eNOS by S-glutathionylation is evident in angiotensin II–induced hypertension.226 Reversal of eNOS uncoupling reduces blood pressure in hypertensive animals221 or contributes to blood pressure reduction by some antihypertensive drugs.226
Hypercholesterolemia
NADPH oxidases and XO are proposed to be the major sources of superoxide in the coronary artery of hypercholesterolemic patients with CAD.55 Uncoupling of eNOS is likely to be a subsequent event secondary to oxidative stress mediated by NADPH oxidase (and XO) because of oxidation-induced BH4 deficiency. Both native LDL and oxLDL have been shown to stimulate superoxide/peroxynitrite production and to uncouple eNOS.227,228 ROS production from uncoupled eNOS has been shown in LDL-treated endothelial cells, in hypercholesterolemic ApoE-KO mice71 and in hypercholesterolemic patients.72 In addition to the direct effects of LDL on endothelial ROS production, hypercholesterolemia may indirectly enhance oxidative stress by potentiating the effects of angiotensin II via upregulation of AT1 receptor.229
In addition to BH4 deficiency, l-arginine deficiency also represents a cause of eNOS uncoupling in hypercholesterolemia. An upregulation of arginase expression and activity has been shown in ApoE-KO mice (Arg2)230,231 and in hyperlipidemic rabbits (Arg1 and Arg2).232 The aortic arginase activity in ApoE-KO mice is significantly reduced after the removal of the endothelium, suggesting important contribution from endothelial cells.230 The functional relevance of arginase upregulation in atherosclerosis has been shown in ApoE-KO mice. Selective endothelial overexpression of Arg2 induces endothelial dysfunction and enhances atherosclerosis in mice.233 Chronic treatment with an arginase inhibitor for 4 or 8 weeks reduces aortic plaque burden in ApoE-KO mice.230
In addition to eNOS uncoupling, LDL and oxLDL also reduce endothelial NO production by inhibiting eNOS activity.66 Hypercholesterolemia upregulates caveolin abundance, stimulates eNOS translocation to membrane caveolae, and promotes eNOS interaction with caveolin.234 Moreover, LDL also decreases the association of eNOS with Hsp90.228 These effects additively inhibit eNOS activity because caveolin is an inhibiting and Hsp90 a stimulating interaction protein of eNOS. Finally, oxLDL decreases eNOS activity by inhibiting Akt-mediated phosphorylation of eNOS at serine 1177235 or by increased proteasomal degradation of eNOS protein.236
Cigarette Smoking
Cigarette smoke–containing compounds have the potential to active endothelial NADPH oxidase237 and to stimulate mitochondrial oxidative stress.238 The enhanced production of superoxide and peroxynitrite leads to vascular inflammation, DNA damage, and vascular aging.238 Moreover, compounds from cigarette smoke also induce oxidative modifications of LDL, which potentiates the pro-oxidative activity of LDL (oxLDL is more potent in activating NADPH oxidase than native LDL).239 BH4 deficiency and eNOS uncoupling have been documented in smokers and supplementation with BH4 can reverse eNOS uncoupling and improve endothelial dysfunction in smokers.75
Diabetes Mellitus
Hyperglycemia stimulates ROS production from different cellular sources. Among these, the mitochondrial electron-transport chain is likely to represent the initial superoxide producer.240 Mitochondria-derived superoxide overproduction leads to activation of protein kinase C and formation of advanced glycation end products.240 Protein kinase C and advanced glycation end products can activate NADPH oxidase and, at the same time, inhibit eNOS activity through post-translational modifications.241
Protein kinase C–stimulated NADPH oxidase activation and eNOS uncoupling have been observed in streptozotocin-induced type 1 diabetes mellitus.242 This is likely to be attributable to NADPH oxidase–mediated BH4 oxidation. Indeed, BH4 oxidation and BH4 deficiency are evident in streptozotocin-treated mice243 and rats.244 In addition, diabetes mellitus also causes BH4 deficiency by reducing BH4 synthesis. Enhanced ROS production in diabetes mellitus accelerates proteasomal degradation of guanosine 5′-triphosphate cyclohydrolase I, a rate-limiting enzyme in the synthesis of BH4.245–247 In addition, eNOS S-glutathionylation represents another important mechanism of eNOS uncoupling in the setting of type 1 diabetes mellitus.247
In mouse models of type 2 diabetes mellitus, a relative BH4 deficiency is evident because of an enhanced BH4 oxidation and a low BH4:BH2 ratio.248–250 The increased levels of angiotensin II in diabetic patients may additionally reduce dihydrofolate reductase expression and decrease BH4 recycling from BH2.222
l-Arginine deficiency represents another mechanism for eNOS uncoupling under conditions of diabetes mellitus. High glucose upregulates Arg1 in (bovine and murine) endothelial cells,251,252 whereas persistent insulin stimulation upregulates the expression and activity of Arg2 in human endothelial cells.253 In addition, l-arginine deficiency and eNOS uncoupling have also been documented in rodent models of type 1251,252,254,255 and type 2 diabetes mellitus.256
In patients with type 2 diabetes mellitus, plasma arginase activity is elevated.257 An upregulation of Arg1 in coronary arterioles of patients with (type 1 or type 2) diabetes mellitus has been shown to contribute to the reduced NO production and consequently diminished vasodilation.258 Arginase inhibition markedly improves endothelium-dependent vasodilation in the forearm of patients with type 2 diabetes mellitus and CAD, whereas it does not affect endothelial function in healthy controls.259 This observation indicates a functional role of arginase contributing to endothelial dysfunction in patients with diabetes mellitus.
Biomechanical Factors
Besides the risk factors at population level (hypertension, hypercholesterolemia, smoking, and diabetes mellitus), disturbed blood flow represents a key risk factor for atherosclerosis within an organism. Atherosclerosis preferentially develops at arches, arterial bifurcations, and side branches, regions that are exposed to nonuniform, disturbed patterns of blood flow.260 Several studies have demonstrated the causal relationship between disturbed flow and atherosclerosis. Disturbed flow induced by applying a constrictive cuff261,262 or by partial ligation or tandem ligations263,264 leads to rapid development of atherosclerosis in the carotid artery, which is otherwise resistant to atherogenesis.
In each cardiac cycle, arteries are exposed to perpendicular and longitudinal forces generated by intraluminal pressure, and axial stress (shear stress), which acts longitudinally on the surface of the arterial wall.260 Whereas laminar flow (with a high shear stress parallel to the vascular wall and a low circumferential strain) is atheroprotective, disturbed flow (with a change in the diameter and proximity to bifurcations) is proatherogenic.260,265,266 Endothelial cells exposed laminar flow show higher endothelia NO production and are resistant to inflammatory signals and have low intercellular permeability.265 In contrast, endothelial cells exposed to disturbed flow show a proinflammatory phenotype with higher ROS production, elevated cell turnover, increased cell-cell permeability, and upregulated expression of adhesion molecules and chemokines.265
Laminar flow enhances endothelial NO production267 by stimulating eNOS phosphorylation at serine 1177268,269 and thus increasing the sensitivity of the enzyme to Ca2+ so that the enzyme can be activated at resting Ca2+ levels.270 In addition, shear stress also upregulates eNOS expression.271 In contrast, disturbed flow or oscillatory shear stress decreases eNOS expression and activity.272,273
On the contrary, oscillatory shear stress markedly increases endothelial superoxide production,274 with NADPH oxidase being the primary superoxide source.9,275 Importantly, NADPH oxidases serve a role as a master oxidase and promote ROS production from other enzymatic sources, eg, XO.9 Xanthine oxidoreductase exists in 2 forms: xanthine dehydrogenase (XDH) and XO. XDH can be converted to XO by reversible sulfhydryl oxidation or by irreversible proteolytic modification.276 In endothelial cells, oscillatory shear stress leads to a NADPH oxidase–dependent degradation of XDH resulting in an increase in XO/XDH ratio. Because both XO and XDH use xanthine as a substrate but only XO generates superoxide, the higher XO/XDH ratio results in enhanced XO-mediated superoxide production.9
Redox Signaling
NO exerts its cellular effects through both cGMP-dependent and cGMP-independent mechanisms. In a cGMP-independent manner, NO modifies protein cysteine residues resulting in an S-nitrosothiol.277 A plethora of proteins (including NADPH oxidase278 and eNOS itself279) undergo S-nitrosylation, which may represent part of the mechanistical explanation of the wide range of cellular effects of NO in the cardiovascular system.277
Protein denitrosylation can be catalyzed by 2 major enzymatic systems. Whereas thioredoxins directly denitrosylate substrate S-nitrosothiol proteins, the S-nitrosoglutathione (GSNO) reductase governs protein S-nitrosylation indirectly by acting on GSNO and thereby modulates the cellular equilibrium between S-nitrosothiol proteins and GSNO.277 Genetic deletion of GSNO reductase increases the levels of S-nitrosothiols in red blood cells and lowers systemic vascular resistance,280 demonstrating the role for GSNO in conveying the systemic activity of NO derived from eNOS.277 Interestingly, the endogenous gaseous signaling molecule hydrogen sulfide also regulates cysteine thiols,281 protects against oxidative stress,282 and has an impact on protein S-nitrosylation,283,284 including S-nitrosylation of eNOS.285
Cysteine is a unique amino acid because of its thiol side chain, which is redox active. Numerous reactions are known to occur on cysteine thiol side chains that affect protein structure and function, including S-nitrosylation, S-sulfhydration (modification by hydrogen sulfide), S-glutathionylation, and disulfide bond formation. Moreover, stepwise oxidation of cysteine thiol by hydrogen peroxide results in the formation of sulfenic acid, sulfinic acid, and sulfonic acid.286,287 Physiological conditions (NO>ROS) favor S-nitrosylation, whereas NO/ROS disequilibrium under oxidative stress favors oxidation reactions (S-glutathionylation, intramolecular disulfide, and sulfur oxides formation).154 Thiol oxidation adversely impacts S-nitrosylation signaling.154 Indeed, disruption of protein S-nitrosylation has been documented under conditions of heart failure154,277 and high glucose.288
Effects of ROS and NO in Key Steps of Atherosclerosis: The Molecular Links
ROS and NO are implicated in the initiation and propagation of atherosclerosis, which provides an explantation how cardiovascular risk factors promote atherogenesis.
LDL Accumulation in the Vascular Wall
As mentioned above, atherosclerosis develops in the arterial system initially at predilection sites with geometries, such as arches, branches, and bifurcations.289,290 One mechanism linking the disturbed flow patterns to atherogenesis is LDL accumulation in the vascular wall.
Theoretically, accumulation of LDL in the artery wall can be caused either by an increase in lipoprotein influx (increase in endothelial permeability and delivery of LDL into the artery wall) or a decrease in lipoprotein efflux caused by an increased binding LDL by the artery wall.
LDL transport from the circulation to the vessel wall is promoted at sites of disturbed flow because of flow stagnation and the subsequent prolonged contact between blood and vascular endothelial cells.260,266 Moreover, structural examination of macromolecular structures reveals that a nearly confluent elastin surface layer is present throughout mouse aorta. This internal elastin layer, however, is missing at vascular branch points, which are among the sites most prone to atherosclerosis.291 LDL binding is most extensive in the arterial branch points where the elastin layer is absent,291 indicating that the absence of an elastin layer contributes to the initial LDL infiltration at these sites and the subsequent development of atherosclerosis.
A recent study has provided compelling evidence that LDL retention represents a mechanism that could be even more important than LDL influx for LDL accumulation in flow-disturbed vascular regions.289 Infusion of normocholesterolemic mice with labeled human LDL results in LDL retention in the intimal and medial layers along the inner curvature of the aortic arch and at branch points.289 The straight segment of the common carotid artery is exposed to uniform laminar flow and is resistant to atherosclerosis. Normally, no LDL retention is found in this region.289 Implanting a mildly constrictive perivascular collar evokes disturbed laminar flow in the segment proximal to the collar characterized by low wall shear stress and cyclic circumferential stretching.292 Strikingly, this manipulated blood flow in the straight segment of the common carotid artery is sufficient to transform this otherwise atherosclerosis-resistant site into LDL-retaining regions. Importantly, the accumulation of LDL in the flow-manipulated region is a result of enhanced LDL binding by the vascular wall without any changes in endothelial permeability or LDL influx.289 Gene expression analyses have revealed that flow manipulation leads to increased expression of proteoglycan core proteins associated with LDL binding and retention.289
The expression of proteoglycans is upregulated after vascular injury293 and in insulin resistance294 associated with increased cholesterol deposition in the vascular wall. Proatherogenic molecules such as platelet-derived growth factor stimulates proteoglycan synthesis in VSMC and enhances LDL retention in blood vessels.295,296 Interestingly, proteoglycans secreted from statin-exposed cells demonstrate a reduction in LDL-binding affinity. Thus, the atheroprotective effects of statins may be partly attributed to changes in vascular proteoglycans and lower LDL retention in the vessel wall.297
The roles of NO and oxidative stress in LDL accumulation in the vascular wall have not been sufficiently studied to date. Previous studies have shown that endothelial NO prevents the uptake of LDL by arterial walls.298,299 Disturbed flow is known to reduce endothelial NO production300 and enhance ROS production in endothelial cells and in VSMC.9,274,301,302 However, the precise roles of NO and ROS in LDL uptake and LDL binding (eg, regulation of proteoglycan expression) are still unknown and warrants future studies.
LDL Oxidation
Experimental studies have demonstrated that oxLDL within the arterial wall promotes atherogenesis,303–305 although direct evidence for the role of LDL oxidation in human atherosclerosis is still rare306 and many questions remain to be answered.305
OxLDL exhibits a wide array of proatherogenic properties.304 Many of these effects are mediated by oxidized phospholipids within the LDL molecules.304 Lipid peroxidation can occur through nonenzymatic mechanisms (eg, by ROS derived from NADPH oxidase or uncoupled eNOS)307 or through enzymatic mechanisms (eg, by myeloperoxidases, lipoxygenases, cyclooxygenases, and cytochrome P450).308 The lipid peroxidation products, such as malondialdehyde, 4-hydroxynonenal, phosphocholine of oxidized phospholipid, and 2-(ω-carboxyethyl) pyrrole, are highly reactive. They modify self-molecules leading to the generation of structural neoepitopes termed oxidation-specific epitopes (OSEs).308 OSEs, including oxidized phospholipids and malondialdehyde-modified amino groups, have been documented on the surface of apoptotic cells and oxLDL molecules.303,308
Peroxidation of phospholipids promotes a conformational change in the apoB-100 molecule leading to increased nonreceptor-mediated capture of the oxLDL particle by vascular cells.303 Moreover, OSEs are recognized by both cellular (eg, scavenger receptors and toll-like receptors [TLRs]) and soluble pattern recognition receptors (eg, proteins of the complement system, C-reactive protein, and natural IgM antibodies).308
The recognition of OSEs by cellular and humoral immune responses has important physiological roles in maintaining tissue homeostasis by removing dying cells, cellular debris, and damaged molecules.308 In situations of increased oxidative stress, however, OSEs generation is significantly increased. Furnished with a variety of scavenger receptors and TLRs, endothelial cells, and macrophages are the major cellular sensors of OSEs in atherosclerosis. Consequently, the persistent sensing of OSEs by these cells triggers chronic inflammation through the secretion of chemokines and proinflammatory cytokines (see below).
The role of LDL oxidation in atherogenesis has been shown in gene targeting studies.304 Genetic deletion of lipoxygenases decreases LDL oxidation and atherosclerosis lesion in mouse models of atherosclerosis.309–312 Disruption of paraoxonase 1, an enzyme that indirectly inhibits LDL oxidation, increases LDL oxidation and lesion formation.313 Moreover, OSE-specific natural IgM antibodies block the binding and uptake of oxLDL by macrophages, prevent foam cell formation,314 and decrease atherosclerosis in mice.315,316 Patients with lower levels of IgM antibodies directed against malondialdehyde-LDL and oxLDL show an increased risk of cardiovascular disease.317
Interestingly, lipid peroxidation also leads to the formation of highly reactive γ-ketoaldehydes (isoketals). Proteins oxidatively modified by isoketals are formed in hypertension and accumulate in dendritic cells. Peptides derived from isoketal adducts of proteins behave as modified self-antigens, activating dendritic cells and T cells, which has been recently identified as a novel mechanism in hypertension.318,319
As aforementioned, NADPH oxidase–derived ROS are involved in LDL oxidation.275 Interestingly, results from bone marrow transplantation experiments in mice indicate that NADPH oxidase in infiltrating immune cells in the vascular wall may be of more importance in LDL oxidation than those in the resident cells of the vascular wall.49 In contrast, endothelial NO has been shown to inhibit LDL oxidation320,321
Endothelial Cell Activation and Adhesion Molecule Expression
Endothelial cells can sense OSE and take up oxLDL via the lectin-like oxidized LDL receptor-1, TLR2, and TLR4.303,308 This may lead to a variety of biological effects, such as (1) reduction of endothelial NO production, (2) upregulation of leukocyte adhesion molecules, (3) promotion of a prothrombotic surface, and (4) synthesis of smooth muscle cell mitogenic factors.303
OSE sensing by endothelial cells is a key response in the development of atherosclerosis.308 Oxidized phospholipids, for instance, induce the expression of chemoattractants (eg, MCP-1 [monocyte chemoattractant protein-1], chemokine (C-X-C motif) ligand 8 and P selectin) and trigger monocyte binding to endothelial cells via TLR4.307 4-hydroxynonenal induces nuclear factor-κB activation in endothelial cells which is mediated by LOX1.322 2-(ω-carboxyethyl) pyrrole has been shown to activate endothelial cells by stimulating TLR2.323 Deficiency of LOX1324,325 or TLR2326 reduces vascular cell adhesion molecule-1 expression and atherosclerosis in LDL receptor-KO mice.
The expression of adhesion molecules by endothelial cells is inhibited by laminar shear stress,327 but enhanced by disturbed flow.328,329 In addition, endothelial expression of adhesion molecules is also upregulated by proatherogenic stimuli, such as proinflammatory cytokines,330,331 angiotensin II,332 advanced glycation end products,333 and leptin.334 Interestingly, the anti-inflammatory adipokine, adiponectin, inhibits the expression of adhesion molecules in endothelial cells and prevents leukocyte–endothelium interaction.335
NO and ROS have opposite roles in the regulation of adhesion molecule expression and endothelial–leukocyte interaction. Endothelial NO inhibits cytokine-induced nuclear factor-κB activation and upregulation of vascular cell adhesion molecule-1, E-selectin, and intercellular adhesion molecule-1.132,331,336–338 Inhibition of NO production increases leukocyte adherence, indicating that endothelial NO is an endogenous modulator of leukocyte adhesion to vascular endothelium.339 On the contrary, ROS are implicated in upregulation of adhesion molecules induced by cytokines330,331 or by leptin.334 ROS not only potentiate OSE sensing by upregulation of endothelial TLR2 expression,326 but are also involved in the intercellular signaling cascades leading to adhesion molecules expression induced by stretch or oscillatory shear stress.340,341
In agreement with this concept, targeted delivery of SOD to endothelial cells in mice inhibits nuclear factor-κB signaling and vascular cell adhesion molecule-1 expression.342 In contrast, genetic disruption of peroxiredoxin1343 or GPx1344 potentiates chemoattractant expression and leukocyte–endothelial cell adhesion.
Macrophage Activation and Foam Cell Formation
A hallmark of atherosclerosis is the formation of foam cells due to enhanced uptake of oxLDL by macrophages mediated by OSE binding to scavenger receptors (eg, CD36, TLRs, SRA1 [scavenger receptor A1] and lectin-like oxidized LDL receptor-1).308,345 OxLDL is taken up much more rapidly than native LDL by monocytes/macrophages.304 The scavenger receptors are not downregulated by intracellular LDL, allowing progressive accumulation of cholesterol to the point of foam cell generation.304
The uptake of oxLDL by macrophages has an important physiological role, as this facilitates oxLDL removal.308 However, under pathological situations, the enhanced uptake of cholesterol-rich LDL and subsequent inefficient removal of intracellular cholesterol can trigger signaling pathways that induce the secretion of inflammatory chemokines and cytokines.308 SRA and CD36 account for ≈90% of macrophage uptake of oxLDL. Genetic disruption of either CD36 or SRA1 reduces atherosclerosis in mice.304,345,346 Supersaturation of cholesterol in macrophages results in the formation of cholesterol crystals leading to the damage of lysosomes, inflammasome activation, and interleukin-1β secretion.347 Excessive foam cell formation induces macrophage apoptosis as observed in advanced atherosclerotic lesions.308,348
Oxidative stress plays a crucial role in macrophage activation and foam cell formation. ROS derived from NADPH oxidase and uncoupled eNOS are involved in the generation of OSE.307 Moreover, XO also plays an important role in cholesterol crystal-induced ROS formation and inflammatory cytokine release by macrophages. XO inhibition reduces arterial ROS levels, improves endothelial dysfunction, and suppresses plaque formation in ApoE-KO mice.51
Therapeutic Strategies
Despite the role of oxidative stress in the pathogenesis of atherosclerosis and other diseases, dietary antioxidant supplements to human subjects do show preventative or therapeutic effect. In a large meta-analysis, antioxidant supplements show no benefit (vitamin C and selenium) or even increase mortality (beta carotene, vitamin A, and vitamin E).349,350
However, the ineffectiveness of the antioxidant therapy does not disprove the role of oxidative stress in atherogenesis. Rather, the used antioxidant compounds are likely to be unspecific, not correctly dosed, cannot reach the intracellular compartment of ROS generation, and some may even have pro-oxidative properties.4,351,352 Therefore, better antioxidant strategies need to be developed.
Among the ROS-producing enzymes, NADPH oxidases are proposed to be the master oxidases.9 NADPH oxidase activation promotes ROS production from other sources. Therefore, NADPH oxidases represent attractive therapeutic targets. However, because of the protective role of Nox4 shown in recent studies, a promising Nox inhibitor should be specific for Nox1 or Nox2. Nox inhibitors with improved specificity for NADPH oxidases and moderate Nox isoform selectivity have been developed.353 The first results in mouse atherosclerosis models are encouraging.
In addition to inhibition of XO activity51 and prevention of mitochondrial oxidative stress,354 pharmacological reversal of eNOS uncoupling represents further fascinating strategies. Among the drugs currently in clinical use, inhibitors of the renin–angiotensin–aldosterone system, statins, nebivolol, and pentaerythritol tetranitrate have been shown to prevent or reverse eNOS uncoupling under experimental conditions. Other compounds, such as resveratrol, sepiapterin, folic acid, and AVE3085, may also recouple eNOS and improve endothelial function although the long-term benefit of these compounds is still unknown (see our recent reviews66,67,355).
Conclusion
Endothelial NO protects against, whereas vascular oxidative stress promotes, atherosclerosis. Cardiovascular risk factors decrease endothelial NO production and stimulate ROS production from various ROS sources including NADPH oxidases, XO, mitochondria, and uncoupled eNOS. ROS and NO have opposite roles in the process of atherogenesis, such as LDL oxidation, endothelial cell activation, and macrophage infiltration/activation. Prevention of vascular oxidative stress and improvement of endothelia NO production may represent feasible therapeutic strategies in addition to the treatment of established cardiovascular risk factors.
| ApoE-KO | apolipoprotein E-knockout |
| BH4 | tetrahydrobiopterin |
| CAD | coronary artery disease |
| CCA | common carotid artery |
| CEP | 2-(ω-carboxyethyl) pyrrole |
| COX | cyclooxygenase |
| DKO | double knockout |
| eNOS | endothelial nitric oxide synthase |
| GPx1 | glutathione perioxidase 1 |
| GSNO | S-nitrosoglutathione |
| HDL | high-density lipoprotein |
| iNOS | inducible nitric oxide synthase |
| LDL | low-density lipoprotein |
| nNOS | neuronal nitric oxide synthase |
| OSE | oxidation-specific epitopes |
| oxLDL | oxidized low-density lipoprotein |
| ROS | reactive oxygen species |
| SOD | superoxide dismutase |
| TLR | toll-like receptor |
| XDH | xanthine dehydrogenase |
| XO | xanthine oxidase |
Acknowledgments
Original work from the authors’ laboratory contributing to this review was supported by the German Research Foundation (DFG; LI-1042/1–1 and LI-1042/3-1), the German Federal Ministry of Education and Research (BMBF; 01EO1003), and intramural fund (Stufe I) of the Johannes Gutenberg University Medical Center Mainz.
Disclosures
None.
Footnotes
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