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Biomedical subjects

A Sevanian

Publications and source records attributed to A Sevanian.

At least 19 recordsLinked to original sources
PubMed2002

Nitric oxide, cholesterol oxides and endothelium-dependent vasodilation in plasma of patients with essential hypertension.

The objective of the present study was to identify disturbances of nitric oxide radical (.NO) metabolism and the formation of cholesterol oxidation products in human essential hypertension. The concentrations of.NO derivatives (nitrite, nitrate, S-nitrosothiols and nitrotyrosine), water and lipid-soluble antioxidants and cholesterol oxides were measured in plasma of 11 patients with mild essential hypertension (H: 57.8 +/- 9.7 years; blood pressure, 148.3 +/- 24.8/90.8 +/- 10.2 mmHg) and in 11 healthy subjects (N: 48.4 +/- 7.0 years; blood pressure, 119.4 +/- 9.4/75.0 +/- 8.0 mmHg). Nitrite, nitrate and S-nitrosothiols were measured by chemiluminescence and nitrotyrosine was determined by ELISA. Antioxidants were determined by reverse-phase HPLC and cholesterol oxides by gas chromatography. Hypertensive patients had reduced endothelium-dependent vasodilation in response to reactive hyperemia (H: 9.3 and N: 15.1% increase of diameter 90 s after hyperemia), and lower levels of ascorbate (H: 29.2 +/- 26.0, N: 54.2 +/- 24.9 micro M), urate (H: 108.5 +/- 18.9, N: 156.4 +/- 26.3 micro M), beta-carotene (H: 1.1 +/- 0.8, N: 2.5 +/- 1.2 nmol/mg cholesterol), and lycopene (H: 0.4 +/- 0.2, N: 0.7 +/- 0.2 nmol/mg cholesterol), in plasma, compared to normotensive subjects. The content of 7-ketocholesterol, 5alpha-cholestane-3beta,5,6beta-triol and 5,6alpha-epoxy-5alpha-cholestan-3alpha-ol in LDL, and the concentration of endothelin-1 (H: 0.9 +/- 0.2, N: 0.7 +/- 0.1 ng/ml) in plasma were increased in hypertensive patients. No differences were found for.NO derivatives between groups. These data suggest that an increase in cholesterol oxidation is associated with endothelium dysfunction in essential hypertension and oxidative stress, although.NO metabolite levels in plasma are not modified in the presence of elevated cholesterol oxides.

Adult↗
PubMed2001

Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although observational studies suggest that estrogen replacement therapy (ERT) reduces cardiovascular morbidity and mortality in postmenopausal women, use of unopposed ERT for prevention of coronary heart disease in healthy postmenopausal women remains untested. OBJECTIVE: To determine the effects of unopposed ERT on the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-based clinic. PATIENTS: 222 postmenopausal women 45 years of age or older without preexisting cardiovascular disease and with low-density lipoprotein cholesterol levels of 3.37 mmol/L or greater (>/=130 mg/dL). INTERVENTION: Unopposed micronized 17beta-estradiol (1 mg/d) or placebo. All women received dietary counseling. Women received lipid-lowering medication if their low-density lipoprotein cholesterol level exceeded 4.15 mmol/L (160 mg/dL). MEASUREMENTS: The rate of change in intima-media thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms obtained at baseline and every 6 months during the 2-year trial. RESULTS: In a multivariable mixed-effects model, among women who had at least one follow-up measurement of carotid intima-media thickness (n = 199), the average rate of progression of subclinical atherosclerosis was lower in those taking unopposed estradiol than in those taking placebo (-0.0017 mm/y vs. 0.0036 mm/y); the placebo-estradiol difference between average progression rates was 0.0053 mm/y (95% CI, 0.0001 to 0.0105 mm/y) (P = 0.046). Among women who did not receive lipid-lowering medication (n = 77), the placebo-estradiol difference between average rates of progression was 0.0147 mm/y (CI, 0.0055 to 0.0240) (P = 0.002). Average rates of progression did not differ between estradiol and placebo recipients who took lipid-lowering medication (n = 122) (P > 0.2). CONCLUSIONS: Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed ERT with 17beta-estradiol than in women taking placebo. Reduction in the progression of subclinical atherosclerosis was seen in women who did not take lipid-lowering medication but not in those who took these medications.

Aged↗
PubMed2001

Loss of apoB-100 secondary structure and conformation in hydroperoxide rich, electronegative LDL(-).

A subpopulation of low-density lipoproteins (LDL) is present in human plasma that contains lipid hydroperoxides and is more negatively charged (LDL(-)) than normal native LDL. By circular dichroism and tryptophan lifetime measurements we found that apoB-100 secondary structure is markedly decreased and its conformation is severely altered in LDL(-). The low tryptophan fluorescence intensity confirms the oxidative degradation of the lipoprotein, and the very long lifetime value of one of its decay components indicates a low polarity environment for the remaining unbleached residues. Either a peculiar folding or, most likely, a sinking of the apoB-100 into the lipid core can account for the observed long lifetime component. Oxidation in vitro produces a similar unfolding of the apolipoprotein but the lifetime of tryptophan fluorescence is shifted to lower values, indicating that the denatured apoprotein remains at the hydrophilic surface of the lipoprotein particle. A disordering and an increased polarity of the LDL(-) surface lipids was demonstrated by measuring the generalized polarization of 2-dimethylamino-6-lauroylnaphthalene (Laurdan). The looser monolayer packing apparently favors the new conformation of apoB-100 and its sinking into a more hydrophobic environment, possibly accounting for it reduced receptor binding properties.

2-Naphthylamine↗
PubMed2001

Hypochlorite induces the formation of LDL(-), a potentially atherogenic low density lipoprotein subspecies.

Oxidation of low density lipoprotein (LDL) induced by hypochlorous acid (HOCl) leading to LDL(-), a minimally oxidized subspecies of LDL, was investigated. LDL(-) is characterized by its greater electronegativity and oxidative status, and is found in plasma in vivo. Its concentration was found to be elevated under conditions that predispose humans to atherosclerosis. We found that HOCl also converts LDL rapidly to an even more oxidized state, identified as LDL(2-), which is more electronegative than LDL(-). After milder oxidation for short durations, formation of LDL(-) takes place while less LDL(2-) is formed. Under these conditions, addition of methionine not only suppressed further oxidation of LDL but also favored the formation of LDL(-) over LDL(2-), possibly by removing chloramines at lysyl residues of LDL. The presence of lipoprotein-deficient plasma did not prevent HOCl-mediated conversion of LDL to more electronegative species. It is concluded that the HOCl-mediated conversion of LDL into more electronegative species might be physiologically relevant.

Arteriosclerosis↗
PubMed2001

Cholesterol oxidation products and fibrogenesis.

Oxidatively modified low density lipoproteins (oxLDL) are known to affect various cellular processes by modulating molecular transduction pathways and signaling nuclear transcription. In particular, the proinflammatory and proatherosclerotic effects of oxLDL are increasingly supported by a multitude of independent but consistent experimental studies. LDL oxidation might be a sequencial process where their lipid moieties are progressively but discretely oxidized, preceding the oxidation/modification of the apolipoprotein domain, an effect that can ultimately result in the uncontrolled uptake of these particles by cells, such as macrophages, and conversion of them to foam cells which is a hallmark of early atherogenesis. These lipoproteins appear to trigger a variety of events which are strongly implicated in the atherogenesis, the pathological process underlying vascular disease.

Arteriosclerosis↗
PubMed2001

Soy and alfalfa phytoestrogen extracts become potent low-density lipoprotein antioxidants in the presence of acerola cherry extract.

Postmenopausal women have an increased risk of coronary heart disease. Oxidation of low-density lipoprotein (LDL) has been implicated in atherogenesis, and the presence of modified LDL (LDL(-)) in plasma appears to represent LDL oxidation in vivo. Because previous studies have demonstrated a strong antiatherogenic effect of estrogen due to its antioxidant activity and similar antioxidant activity was found for specific isoflavones derived from soy extract, the antioxidant activity of a phytoestrogen extract derived from soy and alfalfa was studied. Copper-mediated LDL oxidation was inhibited in the presence of soy and alfalfa extracts, and this effect was further enhanced in the presence of acerola cherry extract, which is rich in ascorbic acid. Male rabbit aortic endothelial cells pretreated with soy extract were resistant to the toxic effects of high levels of LDL and LDL(-), and a lesser, but significant protection, was also afforded by alfalfa extract. Cell-mediated oxidation of LDL, measured by LDL(-) formation, was inhibited in the presence of soy extract but not alfalfa extract. However, in the presence of acerola cherry extract, both soy and alfalfa extracts potently inhibited the formation of LDL(-). These findings show that acerola cherry extract can enhance the antioxidant activity of soy and alfalfa extracts in a variety of LDL oxidation systems. The protective effect of these extracts is attributed to the presence of flavonoids in soy and alfalfa extracts and ascorbic acid in acerola cherry extract, which may act synergistically as antioxidants. It is postulated that this synergistic interaction among phytoestrogens, flavonoids, and ascorbic acid is due to the "peroxidolitic" action of ascorbic acid, which facilitates the copper-dependent decomposition of LDL peroxides to nonradical products; this synergy is complemented by a mechanism in which phytoestrogens stabilize the LDL structure and suppress the propagation of radical chain reactions. The combination of these extracts markedly lowers the concentrations of phytoestrogens required to achieve significant antioxidant activity toward LDL.

Adult↗
PubMed2001

OxLDL induces macrophage gamma-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis.

Oxidized LDL (oxLDL) produced a rapid depletion of intracellular glutathione (GSH) followed by an adaptive increase in J774 A.1 macrophages. OxLDL also induced a transient increase in the levels of gamma-glutamylcysteine synthetase heavy subunit (gamma-GCS-HS), representing the catalytic subunit of the rate-limiting enzyme for de novo GSH synthesis. The induction took place within 3 h, with maximum levels observed by 10 h of treatment. Pretreatment of oxLDL with ebselen inhibited GSH depletion and attenuated the gamma-GCS-HS induction. OxLDL-associated lipid hydroperoxides and their decomposition product aldehydes are two major components thought to account for GSH depletion in macrophages. Ebselen pretreatment had only a minor effect on malondialdehyde levels, whereas peroxide content was essentially abolished, suggesting that oxLDL-associated hydroperoxides may mediate both GSH depletion and gamma-GCS-HS induction. Acetylated LDL (AcLDL) also caused a moderate induction of gamma-GCS-HS protein along with a 30% transient increase in GSH by 3;-6 h, suggesting a minor involvement of scavenger receptor-mediated signaling of GSH synthesis. However, the level of gamma-GCS induction by AcLDL was insufficient to cause a sustained increase in GSH. Macrophages with higher glutathione peroxidase (GPx) activity experienced a more rapid and extensive depletion of GSH when treated with oxLDL under similar conditions, along with greater resistance to oxLDL- or peroxide-induced cytotoxicity. We conclude that oxLDL-associated peroxides are primarily responsible for GSH depletion, creating an oxidizing environment required for gamma-GCS induction and compensatory GSH synthesis. This is facilitated in cells expressing high GPx activity through a rapid depletion of GSH in the face of a peroxide challenge.

Antioxidants↗
PubMed2000

Synergistic inhibition of LDL oxidation by phytoestrogens and ascorbic acid.

Increasing evidence indicates that oxidative modification of low-density lipoprotein (LDL) is an important determinant in atherogenesis, and following menopause, the incidence of coronary heart disease is as prevalent in women as it is in men. Estrogen has been demonstrated to inhibit the susceptibility of LDL to be oxidized, and more recently the use of phytoestrogens has been considered for estrogen replacement therapy. In this study the antioxidant activity of the three major phytoestrogens: genistein, daidzein, and equol were measured in terms of LDL oxidative susceptibility. Increasing levels of genistein, daidzein, and equol inhibited LDL oxidation, and this inhibitory effect was further enhanced in the presence of ascorbic acid. The synergism exhibited by these compounds is of clinical importance to phytoestrogen therapy since the efficacy of phytoestrogens as effective antioxidants is evident at concentration well within the range found in the plasma of subjects consuming soy products. However, this synergism, combined with the low reactivity of the phytoestrogens with peroxyl radicals, suggests that an antioxidant mechanism other then free radical scavenging reactions account for the phytoestrogen antioxidant effect. A structural basis for inhibition of LDL oxidation involving interaction of the phytoestrogens with apoB-100 is postulated.

Adult↗
PubMed2000

Lipid oxidation products in cell signaling.

The recent research on the impact that oxidative changes of biolipids could have in pathophysiology serves to explain how free radical-driven reactions not only are considered as mere toxicologic events, but also modulators of cell activity and function. Oxidatively modified low-density lipoproteins are known to affect various cellular processes by modulating various molecular pathways and signaling nuclear transcription. Among the lipid oxidation products detectable in ox-LDLs, and also in the atherosclerotic plaques, 4-hydroxynonenal has been widely investigated. This aldehyde was shown to upregulate AP-1 transcription factor, signaling through the MAP kinase pathway, with eventual nuclear localization and induction of a series of genes. Further, oxidation products of cholesterol and cholesterol esters, in ox-LDL are of similar interest, especially in relation to the pathogenesis of fibrosclerotic lesions of the arterial wall.

Aldehydes↗
PubMed2000

Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products.

We have previously shown that oxidized low-density lipoprotein (LDL) induces damage to the macrophage lysosomal membranes, with ensuing leakage of lysosomal contents and macrophage cell death. Cholesterol oxidation products (ChOx) have been reported to be the major cytotoxic components of oxidized LDL/LDL- and also to stimulate cholesterol accumulation in vascular cells. In the present study, we characterized the initial events during macrophage damage induced by cholesterol oxidation products (ChOx). Within 24 h of exposure, ChOx caused lysosomal destabilization, release to the cytosol of the lysosomal marker-enzyme cathepsin D, apoptosis, and postapoptotic necrosis. Enhanced autophagocytosis and chromatin margination was found 12 h after the exposure to ChOx, whereas apoptosis and postapoptotic necrosis was pronounced 24 and 48 h after the exposure. Some lysosomal vacuoles were then filled with degraded cellular organelles, indicating phagocytosis of apoptotic bodies by surviving cells. Because caspase-3 activation was detected in the ChOx-exposed cells, lysosomal destabilization may associate with the leakage of lysosomal enzymes, and activation of the caspase cascade. MnSOD mRNA levels were markedly increased after 24 h of exposure to ChOx, suggesting associated induction of mitochondrial protection repair or turnover. We conclude that ChOx-induced damage to lysosomes and mitochondria are sequelae to the cascade of oxysterol cytotoxic events. The early disruption of lysosomes induced by ChOx, with resultant autophagocytosis may be a critical event in apoptosis and/or necrosis of macrophages/foam cells during the development of atherosclerotic lesions.

Animals↗
PubMed2000

The effect of vitamin E, probucol, and lovastatin on oxidative status and aortic fatty lesions in hyperlipidemic-diabetic hamsters.

Diabetes mellitus is associated with an increased risk of premature atherosclerosis, which may be due in part to an increased rate of low density lipoprotein (LDL) oxidation. Previous studies have shown that vitamin E, probucol, and lovastatin can reduce the oxidative susceptibility of LDL in normoglycemic animal models; however, few studies have investigated this in conjunction with aortic fatty streak lesion formation in diabetic hyperlipidemic models. Forty-eight Syrian hamsters were made diabetic by intraperitoneal injection of low dose streptozotocin. Diabetic animals (12 animals/groups) received a high saturated fat and cholesterol diet for 12.5 weeks. At 2.5 week of dietary treatments, the diet was supplemented with either: (1) 500 IU/day vitamin E (D+E); (2) 1% probucol w/w of the diet (D+P); (3) 25 mg/kg lovastatin (D+L); or (4) diabetic control (D). An age-matched group of hamsters (n=6) receiving the same diet but not made diabetic (ND) was used as control. At the end of the study, aortic arch foam cell-rich fatty streak lesion, plasma glucose, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), phospholipids, alpha-tocopherol, plasma lipid peroxide and the susceptibility of LDL to copper-catalyzed oxidation were determined. Diabetes increased plasma glucose, and when combined with an atherogenic diet resulted in a further increase of plasma lipids. Vitamin E, probucol, and lovastatin significantly reduced plasma TG in the diabetic hamsters fed the atherogenic diet. Vitamin E treatment increased TC, probucol reduced HDL-C without affecting TC; whereas lovastatin reduced TC and selectively decreased non-HDL-C, and significantly reduced fatty streak lesion formation in the aortic arch. While vitamin E and probucol were effective in reducing several indices of oxidative stress including plasma lipid peroxides, cholesterol oxidation products and in vitro LDL oxidation, they had no effect on fatty streak lesion formation. Our results indicate that the LDL in diabetic animals is more susceptible to oxidation than in non-diabetic hamsters and that not only vitamin E and probucol but also lovastatin provide antioxidant protection. It appears that in this combined model of diabetes and hypercholesterolemia, progression of fatty streak lesion formation is mainly associated with changes in TC and non-HDL-C as affected by lovastatin, and is less dependent on the extent of LDL oxidation, changes in plasma TG level and oxidative stress status.

Animals↗
PubMed2000

Ascorbic acid enhances 17 beta-estradiol-mediated inhibition of oxidized low density lipoprotein formation.

Postmenopausal women who use estrogen appear to be protected from coronary heart disease (CHD). Studies have demonstrated that estrogen can lower low-density lipoprotein (LDL) levels and the antioxidant activity of 17 beta-estradiol can prevent the oxidation of this LDL. Ascorbic acid is regarded as a major hydrophylic antioxidant, however, its impact on the prevention of CHD has yet to be clearly demonstrated. Modified low density lipoprotein (LDL(-)) is an important marker of LDL oxidation in vivo, since it contributes to the oxidative susceptibility of low density lipoprotein, and at physiological levels displays pro-inflammatory and cytotoxic properties. Previously we showed that women taking estrogen replacement therapy have lower LDL(-) levels along with lower predisposition of the LDL to oxidize. In this study, we evaluated the potential action of 17 beta-estradiol (E(2)) in combination with ascorbic acid (AA) measured on the basis of LDL oxidative susceptibility in vitro and in the presence of cultured cells. High concentrations of E(2) were able to inhibit LDL oxidation, whereas in the presence of ascorbic acid nano- to picomolar levels of E(2) were sufficient to suppress LDL oxidation (P<0.05). Preconditioning male aortic endothelial cells (RAEC) with 5 ng/ml of E(2) (E(2)RAEC) reduced the formation of LDL(-) (P<0.005), and a more extensive inhibition was found in the presence of AA (P<0.0001). Interestingly, E(2) enhanced the uptake of LDL in the absence or presence of AA, however, this was not seen for the uptake of LDL(-). These results provide the first evidence that ascorbic acid can enhance the antioxidant effect of E(2) by preventing LDL oxidation by copper ions or cells. The cytoprotective and antiatherogenic effect of E(2) appears to involve a reduction in the extent of oxidized LDL formation and uptake. The enhanced activity of E(2) in the presence of ascorbate indicates that the antioxidant and antiatherosclerosis activity of E(2) may occur at concentrations within the physiological range.

Adult↗
PubMed2000

Lipid peroxidation in membranes and low-density lipoproteins: similarities and differences.

Lipid peroxidation has been a central aspect of studies of the nature of free radical species and their origin in biological systems. Moreover, there has been a growing interest in lipid peroxidation based on evidence that biologically active products are formed that influence cell function and the course of major human diseases. A review of the work in this area is contributed by Lars Ernster is presented with an emphasis on the mechanisms by which lipid peroxidation is initiated in biological lipid systems. Based on what was described for metal catalyzed oxidation of cell membranes, and the seminal studies on cytochrome P-450-mediated lipid peroxidation, several parallel and distinct aspects of lipid peroxidation are described. A key distinction between lipid peroxidation in cell membranes and lipoproteins reveals aspects of free radical initiated reactions involving proteins and lipids that determine pro- vs. anti-oxidant outcomes, and the role of lipid structure and order in delineating the progress of oxidation.

Animals↗
PubMed2000

Inhibition of LDL oxidation and oxidized LDL-induced cytotoxicity by dihydropyridine calcium antagonists.

PURPOSE: The antioxidant activity of dihydropyridine calcium channel antagonists was evaluated based on LDL oxidation kinetics, oxidative cell injury associated with reactive species generation, and increases in free intracellular calcium (Ca2+) levels. Interactions with ascorbic acid were studied under conditions representative of LDL oxidation in plasma and tissue. METHODS: Analysis of antioxidant activity utilized measurements of one-electron oxidation potentials and scavenging of peroxy radical-mediated oxidation. LDL antioxidant potency was determined spectrophotometrically using copper-mediated oxidation kinetics in the absence and presence of 100 microM ascorbic acid. Prevention of oxidant-induced endothelial cell injury was determined from the formation of reactive oxygen species generation and increases in intracellular free calcium concentrations following addition of oxidized LDL or linoleic acid hydroperoxide. RESULTS: Felodipine and amlodipine effectively inhibit peroxyl radical-mediated oxidation in lipoproteins and cells that is markedly enhanced in the presence of ascorbic acid. In the presence of ascorbic acid, inhibition of LDL oxidation is over four times greater than in LDL treated without antioxidants, and oxidized LDL and linoleic acid hydroperoxide-induced reactive oxygen species formation is effectively suppressed in cells. Inhibition of intracellular calcium increases was achieved using nM concentrations of felodipine or amlodipine. CONCLUSIONS: The additive effect for ascorbic acid and the calcium channel antagonist is postulated to involve a combination of peroxide-degrading and peroxyl radical scavenging reactions, demonstrating the importance of lipid peroxides during LDL oxidation and oxidized LDL-induced cytotoxicity. Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium. Both the cytoprotective and LDL antioxidant activity for these compounds is manifested at concentrations approaching the therapeutic levels found in plasma.

Animals↗
PubMed2000

Oxidant stress in hemodialysis: prevention and treatment strategies.

Oxidant stress has been implicated in a number of pathologies associated with uremia and hemodialysis. These patients have an increased incidence of cardiovascular disease, amyloidosis associated with protein modification, and notable changes in both function and structure of many cellular components. Oxidative reactions most frequently involving free radical intermediates play an important role in these processes and participate both directly and indirectly by further amplification of the inflammatory responses or in activation of signaling cascades mediating proliferation, differentiation, and cell death. Proteins and lipids are susceptible to oxidative degradation. These changes can ultimately alter important structural and functional characteristics and lead to pathological changes. This article addresses some of the diverse mechanisms and pathways involved in these changes, and suggests new therapeutic strategies in preventing oxidative damage.

Humans↗
PubMed2000

Oxidative modification of low-density lipoprotein (LDL) in HD patients: role in electronegative LDL formation.

High cardiovascular mortality in patients on hemodialysis (HD) is largely attributed to oxidative stress and altered lipoprotein profiles. Markedly increased levels of mildly modified LDL subfractions, such as dense LDL and electronegatively charged LDL (LDL(-)), are present in the blood of HD patients and may be markers of atherosclerosis risk. LDL(-), characterized by modified protein content and elevated levels of lipid peroxidation products, is representative of multiple oxidative processes acting on plasma lipoproteins that prevail during HD. In this review, we discussed known mechanisms leading to that may account for oxidative protein modification and/or LDL(-) formation in the context of specific conditions associated with HD.

Anions↗