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Biomedical subjects

C Napoli

Publications and source records attributed to C Napoli.

At least 19 recordsLinked to original sources
PubMed2001

Maternal hypercholesterolemia and treatment during pregnancy influence the long-term progression of atherosclerosis in offspring of rabbits.

Maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in human fetuses and faster progression of atherosclerosis during childhood even under normocholesterolemic conditions. A causal role of maternal hypercholesterolemia in lesion formation during fetal development has previously been established in rabbits. The same experimental model is now used to establish that maternal hypercholesterolemia or ensuing pathogenic events in fetal arteries enhance atherogenesis later in life. Five groups of rabbit mothers were fed chow, cholesterol-enriched chow, or cholesterol-enriched chow plus 1000 IU vitamin E, 3% cholestyramine, or both during pregnancy. Offspring of all groups (n=136) were fed a mildly hypercholesterolemic diet for up to a year and had similar cholesterol levels. Aortic lesion sizes and lipid peroxidation products in plasma and lesions in offspring were determined at birth, 6 months, or 12 months. Lesion progression in offspring of hypercholesterolemic mothers was greater than in all other groups. At each time point, offspring of hypercholesterolemic mothers had 1.5- to 3-fold larger lesions than offspring of normocholesterolemic mothers (P<0.01), with the greatest absolute differences at 12 months. Maternal treatment reduced lesions by 19% to 53%, compared with offspring of untreated hypercholesterolemic mothers (P<0.01), with the greatest effect in the vitamin E groups. At 12 months, lesions in offspring of all vitamin E and cholestyramine-treated mothers were similar to those of normocholesterolemic mothers. Lipid peroxidation end-products in lesions and plasma showed analogous differences between groups as lesions (P<0.01). Thus, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering drugs or antioxidants reduce postnatal lipid peroxidation and atherosclerosis in their offspring.

Animals↗
PubMed2001

High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients.

OBJECTIVES: The study investigated the effects of physical activity on preinfarction angina, a clinical equivalent of ischemic preconditioning (PC), in adult and elderly patients with acute myocardial infarction (AMI). BACKGROUND: Preinfarction angina seems to confer protection against in-hospital mortality in adult but not in elderly patients. However, it has been experimentally demonstrated that exercise training restores the protective effect of PC in the aging heart. METHODS: We retrospectively verified whether physical activity preserved the protective effect of preinfarction angina against in-hospital mortality in 557 elderly patients with AMI. Physical activity was quantified according to the Physical Activity Scale for the Elderly (PASE). RESULTS: In-hospital mortality was 22.2% in elderly patients with preinfarction angina and 27.2% in those without (p = 0.20). When the PASE score was stratified in quartiles (0 to 40, 41 to 56, 57 to 90, >90), a high score was strongly associated with reduced in-hospital mortality (30.8%, 32.2%, 17.2% and 15.3%, respectively, p < 0.001 for trend). Interestingly, a high level of physical activity reduced in-hospital mortality in elderly patients with preinfarction angina (35.7%, 35.4%, 12.3% and 4.23%, respectively, p < 0.001 for trend) but not in those without (23.0%, 27.2%, 26.0% and 35.0%, respectively, p = 0.35 for trend). Accordingly, the protective role of preinfarction angina on in-hospital mortality was present only in elderly patients showing a high level of physical activity (adjusted odds ratio, 0.09; 95% confidence interval, 0.01 to 0.57; p < 0.05). CONCLUSIONS: Physical activity and not preinfarction angina protects against in-hospital mortality in elderly patients with myocardial infarction. Nevertheless, the protective effect of preinfarction angina is preserved in elderly patients with a high level of physical activity.

Age Distribution↗
PubMed2001

Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function.

Up-regulation of proapoptotic genes has been reported in heart failure and myocardial infarction. To determine whether caspase genes can affect cardiac function, a transgenic mouse was generated. Cardiac tissue-specific overexpression of the proapoptotic gene Caspase3 was induced by using the rat promoter of alpha-myosin heavy chain, a model that may represent a unique tool for investigating new molecules and antiapoptotic therapeutic strategies. Cardiac-specific Caspase3 expression induced transient depression of cardiac function and abnormal nuclear and myofibrillar ultrastructural damage. When subjected to myocardial ischemia-reperfusion injury, Caspase3 transgenic mice showed increased infarct size and a pronounced susceptibility to die. In this report, we document an unexpected property of the proapoptotic gene caspase3 on cardiac contractility. Despite inducing ultrastructural damage, Caspase3 does not trigger a full apoptotic response in the cardiomyocyte. We also implicate Caspase3 in determining myocardial infarct size after ischemia-reperfusion injury, because its cardiomyocyte-specific overexpression increases infarct size.

Animals↗
PubMed2001

c-myc activation in early coronary lesions in experimental hypercholesterolemia.

This study tested the hypothesis that c-Myc activation, an oxidation-sensitive transcription factor, and its binding partner Max occurs in coronary arteries of hypercholesterolemic (HC) pigs, and can be attenuated by chronic antioxidant intervention. Coronary arteries were isolated from normal, HC pigs, or HC supplemented with antioxidant vitamins (HC + vitamins). The expression of the c-Myc/Max complex, and its target genes GADD45 and p53, was studied in nonatherosclerotic, early lesions (LL), positively staining for oil-red-O, in adjacent lesion-prone regions (PL), and in healthy segments (HV). The expression of c-Myc and Max in HC was 2- to 3-fold greater in PL, and 4-fold in LL, compared to normal vessels (P < 0.01). The expression of GADD45 was down-regulated, and of p53 increased, in the same regions. These alterations were attenuated in the HC + vitamins. Thus, c-Myc activation is an early atherosclerosis, in both PL and LL coronary arterial regions, and can be blunted by chronic dietary antioxidant intervention.

Animals↗
PubMed2001

Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice.

Restenosis is due to neointimal hyperplasia, which occurs in the coronary artery after percutaneous transluminal coronary angioplasty (PTCA). During restenosis, an impairment of nitric oxide (NO)-dependent pathways may occur. Concomitant hypercholesterolemia may exacerbate restenosis in patients undergoing PTCA. Here, we show that a NO-releasing aspirin derivative (NCX-4016) reduces the degree of restenosis after balloon angioplasty in low-density lipoprotein receptor-deficient mice and this effect is associated with reduced vascular smooth muscle cell (VSMC) proliferation and macrophage deposition at the site of injury. Drugs were administered following both therapeutic or preventive protocols. We demonstrate that NCX-4016 is effective both in prevention and treatment of restenosis in the presence of hypercholesterolemia. These data indicate that impairment of NO-dependent mechanisms may be involved in the development of restenosis in hypercholesterolemic mice. Although experimental models of restenosis may not reflect restenosis in humans in all details, we suggest that a NO-releasing aspirin derivative could be an effective drug in reducing restenosis following PTCA, especially in the presence of hypercholesterolemia and/or gastrointestinal damage.

Animals↗
PubMed2001

Multiple role of reactive oxygen species in the arterial wall.

Increased oxidative stress plays an important role in vascular dysfunction and atherogenesis. Both systemic factors, such as hypercholesterolemia and hyperglycemia, and local factors, such as activation of macrophages and T cells, may contribute to oxidative stress. Oxidation of lipids in lipoproteins and cell membranes leads to functionally important modifications of proteins that affect their recognition by cell surface receptors and protein-protein interactions within the cell, including DNA binding. Oxidized LDL and extracellular oxidation modulate oxidation-sensitive signaling pathways, but it is not clear to what extent this results from receptor-mediated activation or from direct effects on the intracellular redox-balance. Extensive evidence indicates that reactive oxygen species (ROS) regulate gene expression by modulating a large number of transcription factors, including the nuclear transcription factor kappa B (NFkappaB), the peroxisome proliferator activated receptorgamma (PPARgamma), and pathways linked to apoptosis. It is also increasingly recognized that cell differentiation and proliferation, cytokine expression, and programmed cell death are determined by the interactions between oxidation-sensitive regulatory pathways previously thought to lead to distinct outcomes. Because hypercholesterolemia exerts pro-oxidant effects both intra- and extracellularly and because increased ROS formation affects vascular reactivity and atherogenesis by modulating multiple signaling pathways and transcriptional events, future investigations of its atherogenic mechanisms should place greater emphasis on the net effect of such modulation on the expression of a large spectrum of genes. One way of doing this will be by defining clusters of genes responding to hypercholesterolemic stimuli--or interventions with structurally unrelated antioxidants--in analogous ways, irrespective of what regulatory pathway they are controlled by. Microarray technologies that allow simultaneous assessment of large numbers of genes may provide a tool for this approach.

Animals↗
PubMed2001

Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice.

Apolipoprotein E-deficient (apoE(-/-)) and LDL receptor-deficient (LDLR(-/-)) mice develop extensive atherosclerosis, but the occurrence of spontaneous plaque rupture and secondary thrombosis in these models has not been established. The goal of this study was to provide histological evidence of acute complications of atherosclerotic lesions in these mice and to assess their prevalence. Complications of atherosclerosis were initially studied in aortas of control mice which died during previous intervention studies. Coronary arteries and the aortic origin were then systematically assessed in serial sections through the heart of apoE(-/-) and LDLR(-/-) mice. Aortic plaque rupture and/or thrombi were seen in 3 of 82 untreated mice from past intervention studies. Screening of heart sections of 33 older apoE(-/-) mice (age 9-20 months) showed extensive atherosclerosis in one or more coronary arteries of 18 animals. In three coronary arteries, the presence of blood-filled channels within advanced atherosclerotic lesions suggested previous plaque disruption/thrombotic events followed by recanalization. In the aortic origin of the same mice, four deep plaque ruptures (or erosions reaching necrotic core areas) and a large thrombus originating from the core of a disrupted atherosclerotic lesion were observed. Although plaque ruptures/deep erosions were far less frequent than in human populations, these observations demonstrate that spontaneous plaque rupture and secondary thrombosis do occur in apoE(-/-) and LDLR(-/-) mice. These mice may therefore be suitable for studying factors contributing to thrombotic complications of atherosclerosis. However, the frequent absence of a clearly defined single fibrous cap in murine coronary lesions limits their usefulness as a model of fibrous cap rupture.

Animals↗
PubMed2001

Nitric oxide and atherosclerosis.

Endothelial dysfunction has been shown in a wide range of vascular disorders including atherosclerosis and related diseases. Here, we examine and address the complex relationship among nitric oxide (NO)-mediated pathways and atherogenesis. In view of the numerous pathophysiological actions of NO, abnormalities could potentially occur at many sites: (a) impairment of membrane receptors in the arterial wall that interact with agonists or physiological stimuli capable of generating NO; (b) reduced concentrations or impaired utilization of l-arginine; (c) reduction in concentration or activity both of inducible and endothelial NO synthase; (d) impaired release of NO from the atherosclerotic damaged endothelium; (e) impaired NO diffusion from endothelium to vascular smooth muscle cells followed by decreased sensitivity to its vasodilator action; (f) local enhanced degradation of NO by increased generation of free radicals and/or oxidation-sensitive mechanisms; and (g) impaired interaction of NO with guanylate cyclase and consequent limitation of cyclic GMP production. Therefore, one target for new drugs should be the preservation or restoration of NO-mediated signaling pathways in arteries. Such novel therapeutic strategies may include administration of l-arginine/antioxidants and gene-transfer approaches.

Antioxidants↗
PubMed2001

Chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma LDL to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein E knockout mice.

The effects of chronic treatment with the new sulfhydryl angiotensin-converting enzyme (ACE)-inhibitor, zofenopril, in comparison with the classical sulfhydryl ACE-inhibitor captopril or enalapril or placebo on the development of atherosclerosis were determined in apolipoprotein-E knockout (apoE(-/-)) mice. Groups of 2-month-old male mice received either placebo (N=10), 0.05 mg/kg/day of zofenopril (N=10), 1 mg/kg/day of zofenopril (N=10), 5 mg/kg/day of captopril (N=10) or 0.5 mg/kg/day of enalapril (N=8). After 29 weeks of treatment, computer-assisted imaging analysis revealed that zofenopril reduced the aortic cumulative lesion area by 78% at 0.05 mg/kg/day and by 89% at 1 mg/ml/day of zofenopril compared to that of the placebo (P<0.0001). Captopril reduced by 52% aortic lesions compared to placebo (P<0.01 vs. placebo; P<0.05 vs. zofenopril at both doses). Enalapril did not reduce aortic lesions. Furthermore, 0.05 mg/kg/day of zofenopril reduced susceptibility of plasma LDL to in vitro oxidation compared to captopril, enalapril or placebo, as shown by significant reduction of malondialdehyde content (P<0.001 vs. placebo or enalapril; P<0.05 vs. captopril), as well as by the prolongation of lag-time (P<0.01 vs. placebo or enalapril P<0.05 vs. captopril). More importantly, mice treated with 1 mg/ml/day of zofenopril had a significant decrease in the intimal immunohistochemical presence of oxidation-specific epitopes on oxLDL (NA59 monoclonal antibody, P<0.01), macrophages derived foam cells (F4/80 monoclonal antibody, P<0.05) and native LDL (NP monoclonal antibody, P<0.01) compared to placebo, captopril or enalapril. Thus, chronic treatment with the new sulfhydryl ACE-inhibitor zofenopril has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic apoE(-/-) mice. This protection was significantly higher than that reached with captopril and at lower doses of the drug. Treatment with 0.5 mg/kg/day of enalapril did not provide any protective effect.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.

OBJECTIVES: We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. BACKGROUND: Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. METHODS: For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. RESULTS: Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. CONCLUSIONS: This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.

Animals↗
PubMed2001

Effect of glycaemic control and age on low-density lipoprotein susceptibility to oxidation in diabetes mellitus type 1.

BACKGROUND: Although individuals with diabetes mellitus frequently have dyslipidaemias and high blood pressure, much of the increased risk for coronary heart disease is not explained by these and other classical risk factors. Thus, other less widely recognized risk factors, including increased susceptibility of low-density lipoprotein (LDL) to oxidation, might enhance vascular dysfunction and atherogenesis in diabetes. AIMS: We compared both the rate and extent of LDL oxidation ex vivo between 78 poorly controlled individuals with type 1 diabetes and 78 age- and sex-matched non-diabetic controls. We then initiated intensive insulin therapy for 3 months to determine the impact of improved glucose control on LDL composition and oxidation. RESULTS: Diabetic and non-diabetic individuals did not have significantly different body weights, dietary intake, blood pressure, renal function or plasma lipid levels. LDL composition was also similar in both groups. In contrast, vitamin E content in LDL was significantly lower in diabetic patients. Measures of LDL lipid oxidation, including conjugated diene, lipid peroxide and thiobarbituric acid reactive substances formation, as well as measures of LDL protein modification, were significantly greater in diabetic patients. Levels of hyperglycaemia correlated strongly with each measure of LDL lipid oxidation (r ranges from 0.60-0.81, P<0.05 for each correlation). After improved glucose control (average reduction in % Hb(Alc)of 5.5 units) all measures of LDL oxidation improved dramatically and approached values for non-diabetics. Absolute values of LDL oxidation increased among all categories of age in both diabetic and control individuals, and this relationship persisted even after adjustment for differences in glucose concentrations. CONCLUSIONS: We demonstrate that hyperglycaemia has a potent but reversible effect on LDL oxidation and that age may independently enhance LDL susceptibility to oxidation. These pathophysiological effects may play an important role in determining vascular complications and atherogenesis in poorly controlled type 1 diabetic patients.

Adult↗
PubMed2001

Oxidation-sensitive transcription factors and molecular mechanisms in the arterial wall.

Adaptation to various forms of cellular stress involves signal transduction into the cytoplasm and subsequently into the cellular nucleus, and ultimately alteration of gene regulation and expression. Increased oxidative stress, which is associated with increased production of reactive oxygen species and other radical species, plays a pivotal role in vascular dysfunction and contributes substantially to the structural and functional changes leading to vascular disease progression. Activation of oxidation-sensitive transcription factors and molecular mechanisms can be triggered in the systemic, tissue, cellular, and molecular environments, thereby affecting a multitude of pathophysiological events involved in the pathogenesis of atherosclerosis and other vascular diseases. Radicals per se also participate in the pathophysiological vascular response to shear stress and injury. Among the oxidation-sensitive transcription factors, important roles have been ascribed to nuclear factor-kappaB, c-Myc, and the peroxisome proliferator-activated receptor family. Regulation of nuclear events has also been recently proposed to involve corepressor and coactivator molecules. Identification of the genes that are involved in these processes has been facilitated by recent development of microarray chip techniques, which allow simultaneous evaluation of differential gene expression. As many of the transcription factors or their interactions are redox-regulated, antioxidant intervention may affect their bioactivity.

Animals↗
PubMed2001

Mutated p21/WAF/CIP transgene overexpression reduces smooth muscle cell proliferation, macrophage deposition, oxidation-sensitive mechanisms, and restenosis in hypercholesterolemic apolipoprotein E knockout mice.

We have investigated whether by introducing a mutated p21 cyclin-dependent kinase inhibitor through a standard type 5 adenovirus (Ad), it would be possible to interfere with restenosis in hypercholesterolemic apolipoprotein E knockout mice. Restenosis is a clinically relevant, undesired effect of percutaneous transluminal coronary angioplasty (PTCA). A critical event underlying restenosis is smooth muscle cell (SMC) proliferation leading to neointimal formation and vessel reocclusion. Recent data demonstrated that it is possible to reduce restenosis by introducing various genes blocking the cell cycle through Ad vectors. Nonetheless, most experiments were conducted in the healthy carotid artery of rat, which is far from the condition of human disease. Therefore, we investigated whether antiproliferative or proapoptotic genes affect restenosis in a model of atherosclerosis closer to clinical settings. Ad-mutated(m)-p21WAF/CIP1 transgene overexpression induces a significant reduction of restenosis in hypercholesterolemic apolipoprotein E knockout mice subjected to injury of common carotid artery. This was associated with reduced SMC density and proliferation, macrophage deposition, and oxidation-sensitive mechanisms. Treatment with p21/WAF also enhanced TUNEL positivity of arterial cells. We show that in an experimental model of atherosclerosis, braking the cell proliferation through increased vascular apoptosis and reduced oxidation-sensitive signal transduction and macrophage accumulation can significantly ameliorate the deleterious effects of vascular injuries similar to those that occur during PTCA and related procedures.

Adenoviridae↗
PubMed2001

Increased oxidative stress in experimental renovascular hypertension.

The pathophysiological mechanisms responsible for maintenance of chronic renovascular hypertension remain undefined. Excess angiotensin II generation may lead to release of reactive oxygen species and increased vasoconstrictor activity. To examine the potential involvement of oxidation-sensitive mechanisms in the pathophysiology of renovascular hypertension, blood samples were collected and renal blood flow measured with electron-beam computed tomography in pigs 5 and 10 weeks after induction of unilateral renal artery stenosis (n=7) or sham operation (n=7). Five weeks after procedure, plasma renin activity and mean arterial pressure were elevated in hypertensive pigs. Levels of prostaglandin F2alpha (PGF(2alpha))-isoprostanes, vasoconstrictors and markers of oxidative stress, also were significantly increased (157+/-21 versus 99+/-16 pg/mL; P<0.05) and correlated with both plasma renin activity (r=0.83) and arterial pressure (r=0.82). By 10 weeks, plasma renin activity returned to baseline but arterial pressure remained elevated (144+/-10 versus 115+/-5 mm Hg; P:<0.05). Isoprostane levels remained high and still correlated directly with the increase in arterial pressure (r=0.7) but not with plasma renin activity. Stenotic kidney blood flow was decreased at both studies. In shock-frozen cortical tissue, ex vivo endogenous intracellular radical scavengers were significantly decreased in both kidneys. The present study demonstrates, for the first time, that in early renovascular hypertension, an increase in plasma renin activity and arterial pressure is associated with increased systemic oxidative stress. When plasma renin activity later declines, PGF(2alpha)-isoprostanes remain elevated, possibly due to local activation or slow responses to angiotensin II, and may participate in sustenance of arterial pressure. Moreover, oxidation-sensitive mechanisms may influence ischemic and hypertensive parenchymal renal injury.

Animals↗
PubMed2001

Combination of hypercholesterolemia and hypertension augments renal function abnormalities.

Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (n=10) or hypercholesterolemic (n=10) diet, renovascular hypertension (n=7), or combined hypercholesterolemia+hypertension (n=6). The hypercholesterolemic and hypercholesterolemic+hypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemic+hypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6+/-4.7%, P=0.002) but not in hypercholesterolemic or hypertensive animals (8.0+/-7.4% and 8.2+/-5.9%, respectively; P>0.05). Moreover, in the hypercholesterolemic+hypertensive group, cortical perfusion response was further attenuated (2.5+/-4.8%, P=0.02) and significantly different from the group fed a normal diet (P<0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemic+hypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemia+hypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis.

Acetylcholine↗
PubMed2001

Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis occurs later and is less extensive in intracranial arteries than in extracranial arteries. However, the mechanisms responsible are poorly understood. A previous study has suggested a better antioxidant protection of intracranial arteries. METHODS: To assess the influence of age on arterial activity of antioxidant enzymes and atherogenesis, we compared intracranial and extracranial arteries of humans of different ages who retrospectively lacked confounding classic risk factors (48 premature fetuses aged 6.4+/-0.8 months [mean+/-SD], 58 children aged 7.9+/-3.8 years, 42 adults aged 42.5+/-5.1 years, and 40 elderly subjects aged 71.8+/-3.4 years; all males). Lesions were quantified by computer-assisted imaging analysis of sections of the middle cerebral and basilar arteries, the left anterior descending coronary artery, the common carotid artery, and the abdominal aorta. Macrophages, apolipoprotein B, oxidized LDL, and matrix metalloproteinase-9 in lesions were determined by immunocytochemistry. The effect of aging on atherogenesis was then compared with that on the activity of 4 antioxidant enzymes in the arterial wall. RESULTS: Atherosclerosis was 6- to 19-fold greater (P<0.01) in extracranial arteries than in intracranial arteries, and it increased linearly with age. Intracranial arteries showed significantly greater antioxidant enzyme activities than did extracranial arteries. However, the antioxidant protection of intracranial arteries decreased significantly in older age, coinciding with a marked acceleration of atherogenesis. An increase in matrix metalloproteinase-9 protein expression and in gelatinolytic activity consistent with the degree of intracranial atherosclerosis was also observed. CONCLUSIONS: These results suggest that a greater activity of antioxidant enzymes in intracranial arteries may contribute to their greater resistance to atherogenesis and that with increasing age intracranial arteries respond with accelerated atherogenesis when their antioxidant protection decreases relatively more than that of extracranial arteries.

Adult↗