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PubMed1999

Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice.

Antioxidants can inhibit atherosclerosis in animals, though it is not clear whether this is due to the inhibition of aortic lipoprotein lipid (per)oxidation. Coantioxidants inhibit radical-induced, tocopherol-mediated peroxidation of lipids in lipoproteins through elimination of tocopheroxyl radical. Here we tested the effect of the bisphenolic probucol metabolite and coantioxidant H 212/43 on atherogenesis in apolipoprotein E and low density lipoprotein (LDL) receptor gene double knockout (apoE-/-;LDLr-/-) mice, and how this related to aortic lipid (per)oxidation measured by specific HPLC analyses. Dietary supplementation with H 212/43 resulted in circulating drug levels of approximately 200 microM, increased plasma total cholesterol slightly and decreased plasma and aortic alpha-tocopherol significantly relative to age-matched control mice. Treatment with H 212/43 increased the antioxidant capacity of plasma, as indicated by prolonged inhibition of peroxyl radical-induced, ex vivo lipid peroxidation. Aortic tissue from control apoE-/-;LDLr-/- mice contained lipid hydro(pero)xides and substantial atherosclerotic lesions, both of which were decreased strongly by supplementation of the animals with H 212/43. The results show that a coantioxidant effectively inhibits in vivo lipid peroxidation and atherosclerosis in apoE-/-;LDLr-/- mice, consistent with though not proving a causal relationship between aortic lipoprotein lipid oxidation and atherosclerosis in this model of the disease.

Animals↗
PubMed1991

Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation.

Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.

Anticoagulants↗
PubMed2001

Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation.

OBJECTIVES: Considerable attention has been focused on both mildly oxidized low-density lipoprotein (mox-LDL) and highly oxidized LDL (ox-LDL) as important risk factors for cardiovascular disease. Further, angiotensin II (Ang II) appears to play a crucial role in the development of hypertension and atherosclerosis. We assessed the effect of oxidatively modified LDL and its major oxidative components, i.e., hydrogen peroxide (H2O2), lysophosphatidylcholine (LPC), and 4-hydroxy-2-nonenal (HNE) and their interaction with Ang II on vascular smooth muscle cell (VSMC) DNA synthesis. METHODS: Growth-arrested rabbit VSMCs were incubated in serum-free medium with different concentrations of native LDL, mox-LDL, ox-LDL, H2O2, LPC, or HNE with or without Ang II. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. RESULTS: Ang II stimulated DNA synthesis in a dose-dependent manner with a maximal effect at a concentration of 1 micromol/l (173%). Ang II (0.5 micromol/l) amplified the effect of native LDL at 500 ng/ml, ox-LDL at 100 ng/ml, and mox-LDL at 50 ng/ml on DNA synthesis (108 to 234%, 124 to 399%, 129 to 433%, respectively). H2O2 had a maximal effect at a concentration of 5 micromol/l (177%), LPC at 15 micromol/l (156%), and HNE at 0.5 micromol/l (137%). Low concentrations of H2O2 (1 micromol/l), LPC (5 micromol/l), or HNE (0.1 micromol/l) also acted synergisitically with Ang II (0.5 micromol/l) in inducing DNA synthesis to 308, 304, or 238%, respectively. Synergistic interactions of Ang II (0.5 micromol/l) with mox-LDL, ox-LDL (both 50 ng/ml), H2O2 (1 micromol/l), LPC (5 micromol/l), or HNE (0.1 micromol/l) on DNA synthesis were completely reversed by the combined use of probucol (10 micromol/l), a potent antioxidant and candesartan (0.1 micromol/l), an AT1 receptor antagonist. CONCLUSIONS: Our results suggest that mox-LDL, ox-LDL, and their major components H2O2, LPC, and HNE act synergistically with Ang II in inducing VSMC DNA synthesis. A combination of antioxidants with AT1 receptor blockade may be effective in the treatment of VSMC proliferative disorders associated with hypertension and atherosclerosis.

Acetylcysteine↗
PubMed1995

Novel 21-aminosteroidlike compounds prevent iron-induced free radical-mediated injury to vascular endothelial cells.

Free radicals appear to play a major role in the reperfusion injury of the myocardium. Iron chelators and antioxidants can prevent the reperfusion injury. The cellular source of free radicals during reperfusion is not clearly established. However, an important source may be the endothelial cells (EC). The protective effect of iron chelators and antioxidants on reperfusion injury of the myocardium may be partially mediated by their effect on vascular EC, which may attenuate the formation of hydroxyl radicals. We examined the protective effect of deferoxamine and antioxidants on iron-dependent free radical-mediated damage to EC and membrane lipid peroxidation and compared it with those of a new class of compounds (21-aminosteroids: U-74389F, U-74500A, U-78517F) which have both antioxidant and iron chelating properties. We examined viability of the EC and membrane lipid peroxidation using primary aortic EC. First, the effect of increasing iron concentration (0-3.8 microM) (added as ferric ammonium citrate) was characterized. We then examined the effect of deferoxamine (1-10 microM), butylated hydroxytoluene (BHT 1-10 mM), probucol (0.5-5.0 mM), allopurinol (1-1,000 microM), U-74389F (2-20 microM), U-74500A (1-5 microM), and U-78517F (0.1-1.0 microM) on reversing the effect of iron. With increasing iron concentration, there was a significant decrease in the viability of dog aortic or bovine pulmonary arterial EC as compared with NIH 3T3 or human fibroblasts. Equally, there was also a significant increase in lipid peroxidation of the cellular membranes. There were significant differences between the compounds with respect to their ability to maintain the viability of EC and prevent membrane lipid peroxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗
PubMed2003

Direct vascular effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.

1. We have examined the effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on porcine endothelial cell (EC) injury induced by xanthine (X)/xanthine oxidase (XO), a source of superoxide anion. Furthermore, the effects of HR780 on platelet-derived growth factor (PDGF)-induced migration and fetal calf serum (FCS)-induced proliferation of rabbit smooth muscle cells (SMC) were investigated. 2. Probucol, at 10 micro mol/L, significantly (P < 0.001) and completely suppressed lactate dehydrogenase leakage induced by X/XO. At 10 micro mol/L, HR780 significantly (P = 0.010) inhibited X/XO-induced EC injury. 3. HR780 dose-dependently inhibited PDGF-induced SMC migration and FCS-induced SMC proliferation. The addition of mevalonate completely abolished the inhibitory effect of HR780 on SMC proliferation. Another HMG-CoA reductase inhibitor, simvastatin (0.1-100 micro mol/L), also inhibited the migration and proliferation responses as potently as HR780. In contrast, pravastatin (0.1-100 micro mol/L) did not show any effects. 4. This in vitro study provides the first evidence that HR780 protects the vascular endothelium from oxidant stress and inhibits the migration and proliferation of SMC.

Animals↗
PubMedDate not supplied

KR 31372, a benzopyran derivative, inhibits oxidized LDL-stimulated proliferation and migration of vascular smooth muscle cells.

KR 31372 is a benzopyran derivative. Both [3H]thymidine incorporation and migrations (chemotactic and wound-edge) of cultured smooth muscle cells (SMCs) were greatly stimulated by oxidized low-density lipoprotein (LDL). These effects were significantly suppressed by KR 31372 (10(7) - 10(6) M) and PDGF-BB antibody (10(8) - 10(6) M). Preincubation with KR 31372 led to a decrease in the synthesis of PDGF-BB-like immunoreactivity (PDGF-BB-LI) that had been stimulated by oxidized LDL. Otherwise, KR 31372 and probucol strongly inhibited the production of thiobarbituric acid reactive substances (TBARS) caused by the incubation of LDL with Cu2+ ion, and significantly reduced the intracellular oxidative stress when stimulated with H,O2. Taken together, it is suggested that KR 31372 may inhibit the oxidized LDL-stimulated syntheses of DNA and PDGF-BB, and migration of the SMCs, in part, via the antioxidant activity.

Animals↗
PubMed2005

AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid], a novel antioxidant and anti-inflammatory compound: cellular and biochemical characterization of antioxidant activity and inhibition of redox-sensitive inflammatory gene expression.

The pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis, is regulated, at least in part, by modulation of oxidation-reduction (redox) homeostasis and the expression of redox-sensitive inflammatory genes including adhesion molecules, chemokines, and cytokines. AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid] is a novel, orally active, phenolic antioxidant and anti-inflammatory compound with antirheumatic properties. To elucidate its anti-inflammatory mechanisms, we evaluated AGIX-4207 for a variety of cellular, biochemical, and molecular properties. AGIX-4207 exhibited potent antioxidant activity toward lipid peroxides in vitro and displayed enhanced cellular uptake relative to a structurally related drug, probucol. This resulted in potent inhibition of cellular levels of reactive oxygen species in multiple cell types. AGIX-4207 selectively inhibited tumor necrosis factor (TNF)-alpha-inducible levels of the redox-sensitive genes, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, with less inhibition of E-selectin, and no effect on intracellular adhesion molecule-1 expression in endothelial cells. In addition, AGIX-4207 inhibited cytokine-induced levels of monocyte chemoattractant protein-1, interleukin (IL)-6, and IL-8 from endothelial cells and human fibroblast-like synoviocytes as well as lipopolysaccharide-induced release of TNF-alpha, IL-1beta, and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF-alpha-induced nuclear translocation of nuclear factor of the kappa-enhancer in B cells (NF-kappaB), suggesting that the mechanism of action is independent of this redox-sensitive transcription factor. Taken together, these results provide a mechanistic framework for understanding the anti-inflammatory and antirheumatic activity of AGIX-4207 and provide further support for the view that inhibition of redox-sensitive inflammatory gene expression is an attractive approach for the treatment of chronic inflammatory diseases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Relation of vascular oxidative stress, alpha-tocopherol, and hypercholesterolemia to early atherosclerosis in hamsters.

A model of early atherosclerosis in hamsters with moderate hypercholesterolemia (217 to 271 mg/dL) was established that was highly responsive to exogenous antioxidants. A key feature of this model was elevation of vascular oxidative stress by use of a diet deficient in nutritional antioxidants and supplemented with corn oil (10%) and cholesterol (0.2%, 0.4%, or 0.8%). After 10 weeks on the 0.4% cholesterol diet, mean plasma alpha-tocopherol levels declined from 5.68 +/- 0.30 to 1.27 +/- 0.15 micrograms/mL, while monocyte-macrophage foam cell lesions in the aortic arch, as assayed by video microscopy/image analysis of oil red O-stained histological specimens, increased from undetectable at week 0 to 60,900 +/- 5400 microns 2 per specimen at week 10 (mean +/- SEM, n = 36). alpha-Tocopherol or probucol administered for 10 weeks markedly suppressed LDL oxidation ex vivo and profoundly inhibited aortic foam cell formation. However, the effects of antioxidants on aortic lesions were attenuated at higher plasma cholesterol levels, although LDL oxidation ex vivo was effectively inhibited. With a plasma cholesterol level at approximately 250 mg/dL, the maximum effect of alpha-tocopherol on lesion size reached approximately 36% of control value, and the dose for half-maximal effect was approximately 10 mg.kg-1.d-1, which resulted in a plasma alpha-tocopherol value of approximately 20 micrograms/mL. Under these conditions a linear, inverse correlation of aortic lesion size and plasma alpha-tocopherol concentration was observed (n = 68, r = -0.581, P < .001). The data demonstrate that LDL oxidation is a significant component of early atherogenesis in this model but suggest that hyperlipidemia can outweigh the therapeutic effectiveness of antioxidants. The high sensitivity of aortic lesion initiation to alpha-tocopherol in hamsters maintained on moderately hypercholesterolemic diets depleted of endogenous antioxidants demonstrates that vascular oxidative stress can be isolated from other causative factors in an in vivo model of atherosclerosis.

Animals↗
PubMed1996

Improvement of atherosclerosis and stiffness of the thoracic descending aorta with cholesterol-lowering therapies in familial hypercholesterolemia.

The thoracic aorta is frequently involved in atherosclerotic lesions associated with familial hypercholesterolemia (FH). Transesophageal echocardiography (TEE) allows quantitative evaluation of the wall properties of the thoracic aorta. Using TEE, we tested whether atherosclerosis of the thoracic aorta in FH could be improved by cholesterol-lowering therapies. The subjects investigated were 22 FH patients and 22 age-matched normal subjects. The descending aorta (DA) was divided into four longitudinal portions of equal length. Atheromatous lesions of each portion of the DA were scored by character and extension of lesions by biplane two-dimensional TEE. The scores of atheromatous lesions from all four portions of the DA were added together to give the total atheromatous score (TAS). We also measured instantaneous dimensional changes of the DA in a cardiac cycle by M-mode TEE and blood pressure by a cuff method and calculated the stiffness parameter beta (In[SBP/DBP]/[Dmax-Dmin]/Dmin), where SBP is the systolic arterial blood pressure, DBP is the diastolic arterial blood pressure, Dmax is the maximum aortic dimension during the ejection period, and Dmin is the minimum aortic dimension during the preejection period. TAS was higher in FH (3.70 +/- 1.32) than normal (0.62 +/- 0.54, P < .0001) subjects. Beta in FH (10.35 +/- 4.87) was greater than in normal (5.10 +/- 1.25, P < .0001) subjects, but there were no significant differences of DA dimensions between the groups. In both normal subjects and FH patients, beta correlated with age (r = .52, P < .02 and r = .59, P < .005, respectively). In FH patients, beta and TAS correlated well with pretreatment total cholesterol levels (r = .43, P < .05 and r = .60, P < .005, respectively). In 12 of 22 FH patients, strict cholesterol-lowering therapies with diet and cholesterol-lowering drugs (pravastatin and probucol) were undertaken for 13 months. Cholesterol levels were significantly decreased from 333 +/- 45 to 219 +/- 39 mg/dL (P < .0001); this was associated with significant decreases in beta and TAS (from 9.88 +/- 5.03 to 7.88 +/- 3.92, P < .005, and from 3.61 +/- 1.50 to 2.94 +/- 1.22, P < .0005, respectively). In FH patients, the incidence and severity of morphological and physiological atherosclerosis of the DA were significantly higher than in age-matched normal subjects. A significant regression of atherosclerosis was achieved by strict cholesterol-lowering therapies in relatively young FH patients.

Adult↗
PubMed2000

Accumulation of LDL in rat arteries is associated with activation of tumor necrosis factor-alpha expression.

Activation of vascular inflammation in response to hyperlipidemia is believed to play an important role during the early stages of atherogenesis. We demonstrate here that exposure of cultured, rat aortic smooth muscle cells to low density lipoprotein (LDL) stimulated tumor necrosis factor-alpha (TNF-alpha) mRNA and protein expression. Oxidative modification of LDL resulted in a reduction of this stimulatory effect. To analyze whether a similar response also occurs in vivo, we used a recently developed model in which the effects of a rapid accumulation of human LDL in rat arteries can be studied. As previously reported, epitopes specific for human apolipoprotein B began to accumulate in the aorta within 2 to 6 hours after injection of 6 mg of human LDL. This was followed by expression of oxidized LDL-specific epitopes after 12 hours. There was no vascular expression of TNF-alpha at baseline or in phosphate-buffered saline-injected control rats. However, 24 hours after injection of native LDL, there was a marked induction of TNF-alpha mRNA and immunoreactivity in the aorta and other large arteries, whereas injection of oxidized LDL was without effect in this respect. Preincubation of LDL with the antioxidant probucol before injection markedly decreased the expression of TNF-alpha immunoreactivity. The present findings support the notion that LDL may activate arterial expression of TNF-alpha and suggest 1 possible mechanism for the inflammatory response in the early stages of atherosclerosis. The role of LDL oxidation in this process remains to be fully elucidated.

Animals↗
PubMedDate not supplied

Homozygous familial hypercholesterolemia occurring with apoprotein E3 deficiency. Report of two cases.

This is the first report of homozygous familial hypercholesterolemia (FH) occurring together with dysbetalipoproteinemia. The former was demonstrated by deficiency of specific receptors for apoprotein B of low density lipoproteins and the latter by isoelectric focusing of the E isoapoproteins and the presence of a broad-beta band on electrophoresis. Two young boys of Lebanese extraction had extensive tuberous and tendinous xanthomata, serum cholesterol concentrations of 29.9 and 28.4 mmol/liter, respectively, and mildly raised serum triglycerides due to an accumulation of lipoprotein remnant particles. Homozygosity for FH was demonstrated in both boys by the deficiency of specific binding of low density lipoprotein to cultured skin fibroblasts (less than 15% and less than 10% of normal, respectively). The E apoprotein phenotypes showed E3/E2 in one boy and E2/E2 in the other. The treatment of both boys with cholestyramine and probucol reduced the serum cholesterol concentration to between 15 and 18 mmol/liter and dramatically lessened the severity of xanthomatosis.

Apolipoprotein E3↗
PubMed1995

Protection from oxidized LDL-induced leukocyte adhesion to microvascular and macrovascular endothelium in vivo by vitamin C but not by vitamin E.

BACKGROUND: The ability of oxidized LDL (oxLDL) to stimulate leukocyte-endothelium interaction is considered to be an important aspect of its proatherogenic action. Using intravital fluorescence microscopy in the dorsal skinfold chamber model in hamsters, we have previously shown that systemic administration of oxLDL stimulates leukocyte adhesion to microvascular endothelium through a mechanism that involves the generation and action of reactive oxygen species (ROS). METHODS AND RESULTS: Through the combined use of scanning electron microscopy and intravital microscopy in the same animal model, we demonstrate that oxLDL-induced leukocyte adhesion is not confined to the microcirculation but can also be observed on aortic endothelium. OxLDL-induced leukocyte adhesion to both microvascular and macrovascular endothelium was almost entirely prevented by pretreatment of the hamsters with dietary or intravenous vitamin C, which has the capacity to scavenge and neutralize ROS (arterioles: 20.5 +/- 16.4 cells/mm2 [diet] and 16.3 +/- 23.8 cells/mm2 [IV] versus 74.2 +/- 47.5 cells/mm2 [control, P < .01]; aorta: 1.0 +/- 0.4 cells/mm2 [diet] and 1.1 +/- 0.5 cells/mm2 [IV] versus 14.7 +/- 6.0 cells/mm2 [control, P < .01], 15 minutes after oxLDL, n = 7 animals per group). Vitamin C pretreatment also completely prevented oxLDL-induced leukocyte-platelet aggregate formation in the blood-stream but did not affect leukocyte rolling along the microvascular endothelium. No inhibitory effect on any of the studied parameters was observed as a result of pretreatment of the animals with the lipid-soluble antioxidants vitamin E and probucol. CONCLUSIONS: The protective effects of vitamin C on oxLDL-induced leukocyte adhesion and aggregate formation were seen at vitamin C plasma levels that can easily be reached in humans by diet or supplementation, suggesting that this could be one of the mechanisms by which vitamin C contributes to the well-documented protraction of atherogenesis as observed in large epidemiological surveys.

Animals↗
PubMed1999

Doxorubicin selectively inhibits brain versus atrial natriuretic peptide gene expression in cultured neonatal rat myocytes.

Doxorubicin is an antineoplastic agent with significant cardiotoxicity. We examined the effects of this agent on the expression of the natriuretic peptide (NP) genes in cultured neonatal rat atrial myocytes. Doxorubicin suppressed NP secretion, steady-state NP mRNA levels, and NP gene promoter activity. In each instance, brain NP (BNP) proved to be more sensitive than atrial NP (ANP) to the inhibitory effects of the drug. ICRF-187 and probucol reversed the inhibition by doxorubicin of ANP mRNA accumulation and ANP gene promoter activity while exerting no effect on BNP mRNA levels or promoter activity. This represents the first identification of the NP genes as targets of doxorubicin toxicity in the myocardial cell. This inhibition operates predominantly at a transcriptional locus and has more potent effects on BNP versus ANP secretion/gene expression. Measurement of BNP secretion/gene expression may provide a sensitive marker of early doxorubicin cardiotoxicity.

Animals↗
PubMed1999

Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells.

High plasma levels of VLDL are associated with increased risk for atherosclerosis. Here we show that VLDL (75 to 150 microg/mL) activates nuclear factor-kappaB (NF-kappaB), a transcription factor known to play a key role in regulation of inflammation. Oxidation of VLDL reduced its capacity to activate NF-kappaB in vitro, whereas free fatty acids such as linoleic and oleic acid activated NF-kappaB to the same extent as did VLDL. Intravenous injection of human VLDL (6 mg protein per kg) into rats resulted in arterial activation of NF-kappaB as assessed by electrophoretic mobility shift assay. Aortic endothelial cells showed positive nuclear staining for the activated RelA (p65) subunit of NF-kappaB at 6 to 24 hours after injection. There was also a parallel expression of the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, as well as the cytokine tumor necrosis factor-alpha. Pretreatment of the rats with diet containing 1% of the antioxidant probucol for 8 weeks did not inhibit arterial activation of NF-kappaB in response to injection of VLDL. Moreover, injection of triglycerides (10% Intralipid, 5 mL/kg) activated arterial expression of NF-kappaB to the same extent as VLDL. Our results suggest that VLDL may promote the development of atherosclerotic lesions by activation of the proinflammatory transcription factor NF-kappaB. The effect appears to be mediated by a release of VLDL fatty acids but not to involve VLDL oxidation.

Animals↗
PubMed1982

The mechanism of action of lipid-lowering drugs.

In conclusion, many drugs have been used as lipid lowering agents. Only five currently combine efficacy and acceptable side effects. None of these, nicotinic acid, clofibrate, probucol, cholestyramine or colestipol, is without serious drawbacks. In using lipid lowering drugs, it is important to bear in mind the following. First, no patient should be committed to an indefinite period of drug therapy without an adequate trial of diet therapy. For overweight patients, caloric restriction and weight reduction should always be therapeutic goals. Second, as our understanding of lipoprotein metabolism increases, evaluation of new drugs must include not only their effects on triglyceride but also on lipoprotein and apoprotein levels. Third, our drug armamentarium is currently quite limited and there is a pressing need for the development of new, safe and effective hypolipidemic agents.

Cholestyramine Resin↗
PubMed1995

A rapid method for measurement of the susceptibility to oxidation of low-density lipoprotein.

Oxidation of low-density lipoprotein (LDL) may be important in the pathogenesis of atherosclerosis. We describe a method which measures the oxidation resistance of LDL isolated by a rapid procedure without added antioxidants. LDL was isolated from heparinized plasma by density gradient ultracentrifugation and desalted by gel filtration. The protein concentration was standardized to 50 mg/L and oxidation was promoted by copper (2 mumol/L) at 37 degrees C. The total sample preparation time was 2.5 h. Conjugated diene production was monitored at lambda = 234 nm with computation of the lag time. LDL oxidation was inhibited by EDTA but not heparin. Albumin inhibited LDL oxidation but only in concentrations greater than 50 mg/L. LDL was stable in frozen plasma (-70 degrees C) for 10 weeks, but unstable in the isolated and desalted state. The lag time for LDL from patients treated with the antioxidant probucol was markedly prolonged compared to normal subjects.

Albumins↗
PubMed2000

Antioxidant susceptibility of pathogenic pathways in subjects with antiphospholipid antibodies: a pilot study.

The pathogenesis of antiphospholipid antibody (aPL) related thrombosis is multifactorial and includes, amongst others, enhanced coagulation activation measured as prothrombin fragment 1 + 2 (F1 + 2), elevated plasma levels of von Willebrand factor (vWF), plasminogen activator inhibitor (PAI) and endothelin-1 (ET-1) as well as heightened thromboxane generation and lipid peroxidation. To evaluate the antioxidant susceptibility of some of the above pathways, probucol (500 mg/d orally, a cholesterol lowering agent bearing antioxidant properties) was administered for a three week period to 14 subjects with aPL and to seven healthy controls. At baseline aPL participants showed higher plasma levels of vWF (P = 0.006), ET-1 (P = 0.0002) and enhanced urinary excretion of 11-dehydro-thromboxane-B2 (TXB2) (P = 0.0004), F2-isoprostanes (marker of lipid peroxidation) (P = 0.02) and albumin (P = 0.04) than controls. In the aPL group baseline IgG anticardiolipin (aCL) titre positively related with urinary TXB2 (r2 = 0.43, P = 0.01) and inversely with urinary NOx (r2 = -0.6, P = 0.005) whereas urinary NOx and TXB2 were negatively correlated (r2 = -0.42, P = 0.01). After the treatment period significant decreases from baseline values were noted for PAI (P = 0.01), ET-1 (P = 0.006), TXB2 (P = 0.02), F2-isoprostanes (P = 0.01) and albuminuria (P = 0.01) in aPL participants but not in controls. These pilot data support oxidative sensitive mechanisms and a potential role for antioxidant treatment in the pathogenesis of aPL induced vasculopathy.

Adult↗
PubMed2001

Antioxidative effect of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on peroxidation of phospholipid liposomes.

The antioxidative effect of fluvastatin sodium (fluvastatin), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on lipid peroxidation of phosphatidylcholine (PC) liposomes was investigated in various peroxidizing systems. Fluvastatin markedly inhibited the formation of thiobarbituric acid reactive substances in iron (II)-supported peroxidation of liposomes (IC50 = 1.2 x 10(-5) M). The order of magnitude of inhibition of each drug on the peroxidation was: butylated hydroxytoluene > fluvastatin > or = probucol >> pravastatin. Moreover, concentrations of fluvastatin ranging from 1 x 10(-6) to 1 x 10(-4) M inhibited peroxyl radical-mediated peroxidation of liposomes induced by water-soluble and lipid-soluble radical generators, 2,2'-azobis (2-amidinopropane) dihydro-chloride and 2,2'-azobis (2,4-dimethylvaleronitrile), respectively. However, pravastatin showed no effect against peroxyl radical-mediated peroxidation. These results indicate that fluvastatin acted non-enzymatically as an effective inhibitor against lipid peroxidation of PC liposomes and that the antioxidative effects of fluvastatin may be due to the scavenging action of fluvastatin on liposomal lipid peroxidation induced by peroxyl radicals generated in the aqueous and lipid phases.

Antioxidants↗