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Hypercholesterolemia is a common clinical metabolic and/or genetic disorder that promotes functional and structural vascular wall injury. The underlying mechanisms for these deleterious effects involve a local inflammatory response and release of cytokines and growth factors. Consequent activation of oxidation-sensitive mechanisms in the arterial wall, modulation of intracellular signaling pathways, increased oxidation of low-density lipoprotein cholesterol, and quenching of nitric oxide can all impair the functions controlled by the vascular wall and lead to the development of atherosclerosis. This cascade represents a common pathological mechanism activated by various cardiovascular risk factors and may partly underlie synergism among them as well as the early pathogenesis of atherosclerosis. Antioxidant intervention and restoration of the bioavailability of nitric oxide have been shown to mitigate functional and structural arterial alterations and improve cardiovascular outcomes. Elucidation of the precise nature and role of early transductional signaling pathways and transcriptional events activated in hypercholesterolemia in children and adults, including mothers during pregnancy, and understanding their downstream effects responsible for atherogenesis may help in directing preventive and interventional measures against atherogenesis and vascular dysfunction.
Progressive accumulation of evidence over the past 4 decades has shown that elevated plasma cholesterol is an independent risk factor for cardiovascular disease and increased mortality.
Establishment of the National Cholesterol Education Program in 1985 substantially increased the awareness of the risks associated with an elevated cholesterol level and provided guidelines for lipid-lowering therapy.
Despite a decline in mean serum cholesterol levels in the United States and the availability of therapeutic options, about 50% of middle-aged adults still have total cholesterol values higher than desirable,
in populations that previously had a relatively low risk for the disease.
MECHANISMS UNDERLYING CARDIOVASCULAR EFFECTS OF HYPERCHOLESTEROLEMIA
The increased availability of lipids in hypercholesterolemia promotes initiation and progression of atherogenesis in the arterial wall because the oxidative modification and uptake of lipids are not feedback controlled, thus facilitating their excessive uptake.
Indeed, angiographic trials have demonstrated that cholesterol-lowering therapy significantly reduced progression and increased regression of atherosclerotic coronary arterial lesions.
Surprisingly, however, the marked reduction in clinical events far outweighed the relatively modest frequency and magnitude of lesion regression, which may be partly explained by local depletion of lipids and plaque stabilization, with an ensuing decrease in acute coronary events.
Furthermore, the increased incidence of cardiac events associated with hypercholesterolemia in the absence of significantly obstructive CHD has been partly attributed to functional alterations in the arterial wall, such as impaired coronary vascular responses
Indeed, over the past 2 decades it has become apparent that endothelium-dependent vascular relaxation is abnormal in various disease states, including hypercholesterolemia, atherosclerosis, diabetes mellitus, hypertension, and pre-eclampsia, and after heart transplantation.
first demonstrated that intra-coronary infusion of acetylcholine in humans with CHD caused coronary vasoconstriction. Altered vasomotor regulation by the endothelium has subsequently been shown to be an early development of atherogenesis
Cholesterol-lowering treatment is associated with improvement in coronary vascular remodeling and endothelial function in patients with normal or mildly diseased coronary arteries.
Nonetheless, the abnormal regulation of vascular tone may reflect impairment in an array of functions controlled by the vascular wall, such as lipid breakdown, platelet function, coagulation, monocyte adhesion, inflammation, and vessel growth.
The underlying mechanisms responsible for these abnormalities are likely multifactorial, but major contributors that appear to be enhanced during hypercholesterolemia and could be responsible for the early endothelial dysfunction include (1) uncoupling of receptors from G proteins, (2) increased production of oxygen radicals, and (3) decreased availability of L-arginine, a nitric oxide (NO) precursor, coupled with reduced NO production by the damaged endothelium (see subsequent discussion). Indeed, several such events may stem from activation of redox-sensitive mechanisms involved in cellular signaling
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
), increased levels, and subsequent oxidation of low-density lipoprotein (LDL) and oxidative degradation of NO.
Reactive Oxygen Species
A growing body of evidence suggests that numerous pathological conditions are associated with an increased vascular (and to a lesser extent plasma) production of reactive oxygen species (ROS) and other radicals,
This form of pro-oxidant shift in vascular redox status (the so-called oxidant stress), particularly interactions between NO and ROS, represents a common pathological mechanism activated by many cardiovascular risk factors.
Furthermore, ROS seem to serve important cellular signaling mechanisms responsible for many of the features of vascular dysfunction and atherogenic lesion formation.
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
Hypercholesterolemia per se may enhance formation of lipid peroxidative compounds, which are formed when ROS (and/or other radicals) react with increased levels of plasma and tissue lipids. The precipitating events in radical generation during the evolution of atherosclerosis appear to involve early injury to the vascular endothelial layer,
which increases its adhesiveness, permeability, and procoagulation properties, and damage to the intima via formation of oxidized lipoproteins (see subsequent discussion).
Penetration and accumulation in the arterial wall of triglyceride-rich lipoproteins, including very LDL, chylomicrons, and their remnants, activate or induce the synthesis of factors that can initiate inflammatory responses. These include plasminogen activator inhibitor 1 (which may interfere with fibrinolysis), protein kinase C, mitogen-activated protein kinase, and NFκB, which has an important role in the phenotypic modulation of endothelial cells to a proinflammatory condition
In particular, LDL has numerous effects on the endothelium, including those on plasminogen activator inhibitor 1 and induction of adhesion molecule expression
leading to formation of the potent oxidant peroxynitrite and triggering a vicious cycle of oxidation. Subsequent oxidation of LDL yields its oxidized form, which possesses greater efficacy in initiation of superoxide anion production and endothelial dysfunction.
Thus, early injury induces the endothelium to have procoagulant properties; to form vasoactive molecules, cytokines, and growth factors; and to initiate a local inflammatory response that might continue indefinitely.
such as tumor necrosis factor α, interleukin (IL)-1ß, and interferon-gamma, may in turn stimulate ROS-producing enzymes like nicotine adenine dinucleotide phosphate (NADPH) oxidase, the major source of superoxide anion in vascular cells and myocytes,
Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone.
Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone.
which, due to an increase in plasma cholesterol, is released into the circulation where it binds to endothelial cells and sustains production of superoxide anion.
The cellular sources of these species include blood-borne phagocytic cells and infiltrating monocytes (Figure 1), in addition to cells within the vascular wall, such as smooth muscle cells, endothelial cells, and fibroblasts.
Notwithstanding the presence of macrophages and the postulated involvement of superoxide in atherogenesis, its NADPH oxidase-derived source may be from vascular cells because paucity of phagocytic NADPH oxidase does not decrease lesion size in apolipoprotein E- and gp91-phox subunit deficient knock-out mice.
Although cells are normally protected from ROS by antioxidant defense mechanisms, such as the oxygen-radical scavenger enzymes catalase, superoxide dismutase, and glutathione per-oxidase, the rate of ROS formation can exceed the antioxidant defense capacity and thereby increase oxidant stress.
The precise mechanisms whereby cells in the arterial wall produce ROS are only presently coming to light and will almost certainly prove to be a primary focus of future therapeutic strategies.
Figure 1Oxidation-sensitive mechanisms activated in the arterial wall during hypercholesterolemia. Increased availability of native low-density lipoprotein (nLDL) cholesterol and release of reactive oxygen species (ROS) lead to production of “minimally” or “mildly” oxidized LDL (moxLDL) in association with a decrease in bioavailability of nitric oxide (NO). These alterations may interfere with the normal function of the blood vessel and thus induce endothelial dysfunction. Furthermore, increased uptake of moxLDL by the vascular wall results in further oxidation of LDL to an “extensively” modified (eoxLDL) form and subsequent accumulation and macrophage uptake of LDL, which in turn promote inflammatory responses and continued release of ROS. Pro-oxidant effects on endothelial and smooth muscle cells initiate a chain reaction of redox-sensitive transductional and transcriptional events (inset). Activation of both FAS and tumor necrosis factor receptors (TNFR) and the caspase, mitogen-activated protein (MAP) kinase, and JUN kinase pathways lead to stimulation of various oxidation-sensitive transcription factors that have the potential to increase the expression of various cell adhesion molecules and inflammatory gene products. Antioxidants can interfere with this pathophysiological scenario at several points by scavenging or blunting the release of ROS and by retarding LDL oxidation. AP = activator protein; ATF = activating transcription factor; CREB = cyclic adenosine monophosphate response element binding protein; E2F = elongation 2 factor; ELK = ets-like element kinase; IκB = inhibitor of κ B; NFκB = nuclear factor κ B.
The ROS in turn initiate a chain reaction of redox-sensitive signaling events through which they influence vascular smooth muscle cell growth and migration, modulation of vascular function, expression of a proinflammatory phenotype, and modification of the extracellular matrix
As a result, several redox-sensitive transcription factors are stimulated, such as activating transcription factor 2, ets-like element kinase-dependent 1, cyclic adenosine monophosphate response element binding protein, NFκB, activator protein 1 complex, p53, and c-Myc/Max complex and its binding factors elongation 2 factor and activator protein 2 complex
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
(Figure 1). This can lead to increased expression of various cell adhesion molecules and inflammatory gene products, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and monocyte chemo-attractant protein 1. The involvement of ROS in activation of these pathways is underscored by the successful attenuation of these components using antioxidants, both in vitro and in vivo,
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
Accumulating evidence also provides a compelling case for enhanced oxidative stress in vascular dysfunction, the most important manifestation of which is modulation of a set(s) of proinflammatory genes that are regulated directly or indirectly by ROS in the arterial wall.
Viewed in this perspective, LDL oxidation could be an important consequence of a generalized metabolic oxidation-related abnormality of the arterial wall in atherosclerosis, rather than a single core pathophysiological feature. The fact that hypercholesterolemia, hypertension, and advanced glycosylation end products formation linked to diabetes mellitus all activate similar redox-sensitive pro-inflammatory genes associated with the pathogenesis of atherosclerosis and decrease the bioavailability of NO provides the potential for the development of a unifying framework concerning the etiology of atherosclerotic disease.
Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone.
; however, shear stress and vascular hemodynamic stress per se can also trigger redox-sensitive mechanisms and thus contribute to hypertension-induced atherogenesis.
Indeed, activation of intracellular oxidative signals and modulation of vascular proinflammatory gene expression may provide a molecular mechanism underlying the synergism among cardiovascular risk factors and the early pathogenesis of atherosclerosis.
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
The effects of experimental hypercholesterolemia and oxidation-sensitive mechanisms on this cascade of events have been investigated in various animal models, such as murine
Experimental investigation of the development and progression of atherosclerosis has been greatly facilitated by the use of targeted mouse models of the disease, particularly those resulting from the absence of functional genes.
Mice are rapidly becoming a ubiquitous model of atherogenesis, and although wild-type mice are inherently resistant to hypercholesterolemia and atherogenesis, identification of genes determining the susceptibility to the disease and gene-knockout and transgene approaches have led to generation of the apolipoprotein E knockout mouse, LDL-receptor deficient mouse, and double-knockout mouse models that develop extensive atherosclerosis.
The hypercholesterolemic mouse model also facilitated study of the “priming” phenomenon, which involves activation of NFκB-dependent genes in lesion-prone areas.
that in this model hypercholesterolemia was associated with blunted myocardial perfusion and increased vascular permeability responses to increased cardiac demand, accompanied by depletion of tissue endogenous radical scavengers and enhanced oxidizability of LDL, all of which were correctable with long-term antioxidant therapy. We subsequently showed that similar oxidation-sensitive mechanisms were activated in the systemic and renal circulation of the renovascular hypertensive pig model
paralleled by renal perfusion abnormalities. A growing bulk of evidence shows that coronary blood flow and myocardial perfusion are altered in humans with hypercholesterolemia
; they also may be related to the concurrent oxidative stress.
Oxidized LDL
Susceptibility to atherosclerosis is associated with elevations in specific populations of apolipoprotein B–containing particles involving increased oxidation of LDL and associated changes in its biological properties.
Lipoprotein oxidation may be potentiated by the greater mass of oxidizable LDL substrates available in hypercholesterolemia, by a decrease of natural antioxidants bound on LDL, and by a greater intrinsic susceptibility for oxidation of the specific steric forms of LDL (eg, small dense LDL) that arise in these disorders.
Entrapment of the LDL particles within the arterial wall (Figure 1) results in progressive oxidation (to minimally and extensively oxidized forms) and internalization of this modified LDL by an entire family of scavenger receptors on macrophages and smooth muscle cells, which in turn lead to formation of lipid peroxides, activation of inflammatory cytokines, and a vicious cycle of inflammation and oxidation, eventuating in accumulation of lipid-laden foam cells and plaque formation.
The broad cascade of transduction and transcriptional events in the arterial wall induced by 2 forms of oxidized LDL is shown in Figure 1. These pathways activated by minimally and extensively oxidized LDL are probably largely similar to those activated by ROS and other radicals.
Obviously, several “intermediate” forms of oxidized LDL can be formed in the intima with different degrees of both lipid and protein oxidation. Considerable light has been shed on the mechanisms of interaction between hypercholesterolemia and hypertension with the recent discovery of LOX-1,
Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits.
Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors.
provides an additional route for the vicious cycle of pathophysiological events triggered in hypercholesterolemia.
These facets of LDL oxidation are potentiated in several forms of dyslipidemia and, in view of both differences and similarities among these disorders, indicate that LDL oxidative behavior is determined by a complex array of physical, chemical, and metabolic factors.
Oxidized LDL exerts profound effects on the vasomotor response of isolated arteries to various stimuli that closely mimic the vascular dysfunction associated with hypercholesterolemia and atherosclerosis in humans.
The inhibitory effect of oxidized LDL on vascular relaxation may be related to uncoupling of endothelial receptors from endothelial guanine nucleotide-binding regulatory (Gi) protein and interruption of Gi protein-dependent pathways.
combined with the ability of antioxidants to alleviate vasomotor disturbances in hypercholesterolemia and slow the progression of atherosclerosis, strongly supports a causative role of oxidized LDL in mediating vascular dysfunction in vivo and contributing to both preclinical and clinical sequelae of CHD.
Further research for a more complete understanding of the mechanisms of oxidized LDL formation and actions in vivo may reveal novel strategies to inhibit these pathophysiological events and may prove beneficial in the therapeutic management of atherosclerosis-related diseases.
Nitric Oxide
One of the main mechanisms underlying impaired endothelial function in hypercholesterolemia and other cardiovascular risk factors
among which increased superoxide anion production and oxidative stress represent major mechanisms.
Endogenous NO is generated by a family of 3 distinct calmodulin-dependent NOS enzymes. The endothelial (eNOS) and neuronal NOS isoforms are both constitutively expressed enzymes whose activities are stimulated by increases in intracellular calcium. In the endothelium, eNOS converts the amino acid L-arginine to L-citrulline and NO, a reaction that requires availability of both the substrate (L-arginine) and a cofactor, tetrahydrobiopterin, which couples L-arginine oxidation to NADPH consumption.
which can be achieved by modulation of eNOS gene expression (eg, by shear stress or cell proliferation) or activity (eg, by shear stress or stimulation of specific receptors to agonists). Various stimuli for eNOS also alter cellular redox state, suggesting that ROS might modulate eNOS expression.
Recent evidence indicates that, in hypercholesterolemia, increased cholesterol uptake by endothelial cells up-regulates the abundance of the structural protein and signal transduction regulator caveolin-1
Furthermore, in the absence of either L-arginine or tetra-hydrobiopterin (eg, due to tetrahydrobiopterin oxidation by peroxynitrite), eNOS produces superoxide and hydrogen peroxide,
Expression of extracellular SOD and iNOS in macrophages and smooth muscle cells in human and rabbit atherosclerotic lesions: colocalization with epitopes characteristic of oxidized LDL and peroxynitrite-modified proteins.
Its role in atherogenesis is controversial because it appears that iNOS-derived NO can inhibit, have no effect, or enhance leukocyte rolling and adhesion depending on the type of inflammatory response.
Effect of chronic treatment with the inducible nitric oxide synthase inhibitor N-iminoethyl-L-lysine or with L-arginine on progression of coronary and aortic atherosclerosis in hypercholesterolemic rabbits.
Vasculoprotective role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1β in pigs in vivo.
Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats.
Further studies are needed to define more precisely the conditions under which iNOS exerts beneficial or detrimental effects on the development of atherosclerosis.
Modulation of NO-dependent pathways could provide several benefits in negating atherosclerotic lesion formation and progression.
Among the normal functions of NO are inhibition of platelet adherence and aggregation, reduction in adherence of leukocytes to the endothelium, and suppression of vascular smooth muscle cell proliferation.
NO is a potent antioxidant, ROS scavenger, and modulator of inflammatory and signal transduction pathways, which can modulate lipid peroxidation and proinflammatory gene expression.
However, NO and its products, such as reactive nitrogen species, may also exert pro-oxidant effects, like increase membrane and lipoprotein lipid oxidation and foam cell formation. This type of reaction depends on the relative concentrations of NO, ROS, and antioxidants, as well as on the aqueous-lipid solubility and relative rates of reaction of the participating reactive species. Hence, when endogenous tissue rates of oxidant production are accelerated or when tissue oxidant defenses are depleted, NO-derived oxidizing species can promote pro-atherogenic effects.
Therefore, a decrease in the relative bioavailability of NO not only impairs endothelium-dependent vasodilation but also activates other mechanisms that have an important role in the pathogenesis of atherosclerosis.
Patients with hypercholesterolemia have impaired receptor- and endothelium-dependent vascular relaxation, which may predispose coronary arteries to vasoconstriction.
Investigation of decreased availability of nitric oxide precursor as the mechanism responsible for impaired endothelium-dependent vasodilation in hypercholesterolemic patients.
NOVEL TREATMENT STRATEGIES IN HYPERCHOLESTEROLEMIA
Hypercholesterolemia plays a major causal role in atherogenesis, and therefore reduction of blood cholesterol is a primary therapeutic target. Progress has been substantial in identifying pathogenic mechanisms of atherosclerosis, in particular with regard to the role of apolipoproteins and scavenger receptors, adhesion molecules, growth factors, and interleukins.
prevention trials have demonstrated unequivocally the decrease in coronary morbidity and mortality that can be achieved by lowering lipids in patients with hypercholesterolemia. To decrease the rate of cardiac events and mortality, the target goals of therapy are generally to achieve LDL levels of 100 mg/dL or lower in patients with established CHD and 130 mg/dL or lower in high-risk patients without established CHD. Conventional interventions include lifestyle modification (eg, reduced intake of saturated fatty acids and cholesterol and increased physical activity), addressing other concurrent cardiovascular risk factors (such as obesity, hypertension, diabetes, or post-menopause), and drug therapy.
Lipid-lowering drugs include bile acid sequestrants, nicotinic acid, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”), all of which have important roles in cholesterol-lowering therapy, alone or in combination.
The agents with the greatest LDL cholesterol-lowering effect are the bile acid sequestrants, which up-regulate the LDL receptor by interruption of enterohepatic circulation of cholesterol-rich bile acids, and the statins, which interfere with the cholesterol biosynthesis pathway by inhibiting HMG-CoA reductase.
The greatest triglyceride-lowering effect is exerted by nicotinic acid, which decreases the production of very LDL cholesterol and reduces the availability of circulating free fatty acids, and the fibric acid derivatives, which activate hepatic peroxisome proliferator-activated receptor α-1 and lipoprotein lipase, thus improving the plasma transport rates of several lipoproteins, and inhibit inflammatory mediators.
Among these, statins are the most commonly prescribed agents for the treatment of hypercholesterolemia because of their efficacy in reducing both LDL levels and event rates and because of their excellent tolerability and safety.
When this approach does not achieve desired goals in LDL levels, in rare circumstances (such as familial hypercholesterolemia), patients can undergo LDL apheresis, which has been associated with a decreased CHD event rate.
Remarkably, some of the conventional interventions exert their beneficial effects to some extent through attenuation of oxidation-sensitive mechanisms. For example, long-term exercise training may improve bioavailability of NO and endothelium-mediated vasorelaxation,
Notwithstanding an evident need to decrease plasma cholesterol, novel strategies in recent years have attempted to target mechanisms responsible for the outcomes of hypercholesterolemia, with primary goals of both decreasing oxidant stress and increasing bioavailability of NO.
Antioxidant Approaches
The large body of evidence supporting the important contribution of endogenous oxidative stress to the development of early atherosclerosis in humans
Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.
Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study.
Gene expression in macrophage-rich human atherosclerotic lesions: 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.
has led to the use of antioxidant therapy in an attempt to prevent functional and structural vascular damage. In vitro, cellular, and animal studies clearly demonstrate that vitamin E, the most important fat-soluble antioxidant, and vitamin C, a highly potent water-soluble antioxidant,
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
and they can potentially interrupt the downstream sequence of atherogenic events. Clinical intervention trials with long-term antioxidant therapy support the notion that supplemental vitamin E can reduce the risk of myocardial infarction and heart disease,
In particular, the combination of vitamin E (400–1200 IU/d) with moderate doses of vitamin C (ascorbate), which scavenges a wide range of reactive radicals (oxygen, nitrogen species, and others) and regenerates vitamin E,
Long-term effects of vitamin E, vitamin C, and combined supplementation on urinary 7-hydro-8-oxo-2′-deoxyguanosine, serum cholesterol oxidation products, and oxidation resistance of lipids in nondepleted men.
Notably, the efficacy of the widely prescribed HMG-CoA reductase inhibitors in decreasing the incidence of cardiac events and mortality rate is likely enhanced by their possible antioxidant properties,
Their capability to reduce the expression of IL-1β and IL-6, peroxisome proliferator-activated receptor α and γ, and the p22-phox and p47-phox subunits of NADPH oxidase underscores their beneficial anti-inflammatory and antioxidant attributes.
Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells.
During selective LDL apheresis, an increase in plasma glutathione concentrations was observed, which was unaccompanied by a significant reduction in the plasma activity of antioxidant enzymes, LDL, red blood cells, or granulocytes and may explain the lack of plasma lipid peroxidation shown during this kind of extracorporeal treatment.
Moreover, since depletion of L-arginine may contribute to endothelial dysfunction, infusion of L-arginine improves the forearm resistance vessel blood flow responses to methacholine in patients with hypercholesterolemia.
L-arginine supplementation for 6 months in humans also improves coronary small-vessel endothelial function, in association with a significant improvement in symptoms,
Indeed, oral L-arginine led to a significant clinical improvement in 70% of patients with intractable angina pectoris, in association with a significant decrease in cell adhesion molecule and proinflammatory cytokine levels,
suggesting that it may also have anti-inflammatory properties. The mechanisms by which NO bioavailability can be improved with any drug therapy remain to be elucidated and may provide further insights into the mechanisms involved in impaired endothelial function and atherogenesis.
However, a systematic morphometric analysis of the entire aorta of premature human fetuses demonstrated that formation of fatty streaks, the precursors of more advanced atherosclerotic lesions, is prevalent in all fetal aortas and that their number and size are markedly increased in fetuses whose mothers had hypercholesterolemia during pregnancy.
Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.
Fetal lesions contained typical components of early atherosclerotic lesions, such as native and oxidized LDL and macrophages, and their distribution reflected that of more advanced atherosclerosis seen in adults, ie, most extensive in the abdominal aorta, followed by the aortic arch. This suggests that, during the earlier stages of pregnancy, maternal hypercholesterolemia may promote early atherogenesis in the fetus.
in which the middle cerebral and basilar arteries of fetuses contained significantly smaller lesions than the aorta and common carotid arteries. Determinations of the arterial activities of oxygen-radical scavengers, such as manganese superoxide dismutase, catalase, and glutathione peroxidase, indicated that overall intracranial arteries of human fetuses were better protected against oxidation than extracranial arteries.
These results are consistent with the assumption that better protection against free radical–mediated oxidation may contribute to the greater resistance of intracranial arteries to hypercholesterolemia-induced atherogenesis and vascular dysfunction.
To investigate whether fetal lesions regress and/or whether they influence atherogenesis during childhood and adolescence, the Fate of Early Lesions in Children (FELIC) study was designed.
Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study.
Atherosclerosis was established by computer-assisted image analysis in normocholesterolemic children and was found to progress much faster in children whose mothers had hypercholesterolemia during pregnancy than in children of normocholesterolemic mothers, despite normal lipid profiles in both groups of children. None of the risk factors of atherogenesis assessed in these children could account for the faster atherogenesis in children of hypercholesterolemic mothers. Although parental genetic differences are likely to contribute to the different susceptibility of children to the disease, we postulated that maternal-fetal hypercholesterolemia induced constitutive changes in gene expression in arterial cells, which were associated with a greater susceptibility to the disease later in life.
A recent study demonstrated that fetal lesions in the rabbit can be reduced with vitamin E or cholestyramine treatment of the hypercholesterolemic mothers during pregnancy.
Maternal hypercholesterolemia enhances atherogenesis in normocholesterolemic rabbits, which is inhibited by antioxidant or lipid-lowering intervention during pregnancy: an experimental model of atherogenic mechanisms in human fetuses.
Maternal hypercholesterolemia during gestation should therefore be added to the list of risk factors determining the need for monitoring and for preventive therapy.
although such screening would not detect an increased risk associated with maternal hypercholesterolemia in normocholesterolemic subjects. An intense lipid-lowering intervention may be a therapeutic option for children with several risk factors. As indicated by a recent meta-analysis of studies on the development of coronary artery disease in children and adolescents,
an average reduction of LDL cholesterol by 25% can be obtained with statins in combination with a lipid-lowering diet. Statins are generally well tolerated in children and adolescents, and current data do not indicate adverse effects on growth and sexual development in male adolescents. In high-risk children, follow-up may need to include an attempt for an earlier than usual noninvasive diagnosis of atherosclerosis. Potential approaches include measurement of coronary flow velocity in the distal left anterior descending (LAD) coronary artery with transthoracic Doppler echocardiography,
Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color Doppler echocardiography.
Use of the continuity equation for transesophageal Doppler assessment of severity of proximal left coronary artery stenosis: a quantitative coronary angiography validation study.
Validation of a new noninvasive method (contrast-enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire.
Another clinical scenario that may involve dyslipidemia and oxidative stress is the pregnancy-related preeclampsia syndrome, the etiology and pathogenesis of which remain poorly understood.
Recent evidence points to a pro-oxidant shift in preeclampsia, and ROS and/or their metabolites have been hypothesized to ultimately compromise the vasodilatory, antiaggregatory, and barrier defense functions of the endothelium. Failure of flow-induced shear stress may contribute to the gestational hypertension of preeclampsia.
Oxidative stress as a result of interaction of fetoplacental and maternal factors and autoimmune reaction may lead to the manifestations of preeclampsia. For example, interaction of maternal neutrophils and oxidized lipids with placental cells and placenta-derived factors can engender a vicious cycle of oxidative stress that may ultimately cause widespread endothelial cell dysfunction and physiological perturbations downstream of cellular signaling. A randomized controlled trial recently showed that vitamin C and E supplementation may be beneficial in women with or at increased risk for preeclampsia,
suggesting that the “primum movent” of the disease was increased lipid oxidation during pregnancy.
CONCLUSIONS
Hypercholesterolemia is a common clinical disorder that may begin early in life in humans, and it subsequently promotes atherogenesis by injuring the vascular wall, thereby impairing a multitude of functions and signaling pathways that it controls and leading to development of atheromatous plaques. The underlying mechanisms responsible for these abnormalities may emanate from activation of oxidation-sensitive mechanisms, increased oxidation of LDL cholesterol, and quenching of NO. This cascade of events can begin as early as during pregnancy, altering the complex framework of signaling network in the arterial wall. Novel treatment strategies that attempt to decrease oxidation and restore bioavailability of NO have the potential to decrease morphologic and functional arterial damage and improve cardiovascular outcomes in patients with hypercholesterolemia.
Acknowledgments
We dedicate this article to the memory of Dr Russell Ross who died on March 18, 1999. We thank Drs Wulf Palinski and Filomena de Nigris for valuable discussions in the field.
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Cholesterol-lowering treatment is associated with improvement in coronary vascular remodeling and endothelial function in patients with normal or mildly diseased coronary arteries.
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone.
Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits.
Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors.
Expression of extracellular SOD and iNOS in macrophages and smooth muscle cells in human and rabbit atherosclerotic lesions: colocalization with epitopes characteristic of oxidized LDL and peroxynitrite-modified proteins.
Effect of chronic treatment with the inducible nitric oxide synthase inhibitor N-iminoethyl-L-lysine or with L-arginine on progression of coronary and aortic atherosclerosis in hypercholesterolemic rabbits.
Vasculoprotective role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1β in pigs in vivo.
Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats.
Investigation of decreased availability of nitric oxide precursor as the mechanism responsible for impaired endothelium-dependent vasodilation in hypercholesterolemic patients.
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