Biomedical subjects

W Palinski

Publications and source records attributed to W Palinski.

At least 73 records · Page 4Linked to original sources

PubMed1995

Increased autoantibody titers against epitopes of oxidized LDL in LDL receptor-deficient mice with increased atherosclerosis.

Increasing evidence indicates that immune processes modulate atherogenesis. Oxidized LDL (Ox-LDL) is immunogenic, and autoantibodies recognizing epitopes of Ox-LDL have been described in plasma and in atherosclerotic lesions of several species. To determine whether the titer of such autoantibodies correlates with the extent of atherosclerosis, we followed the development of antibodies against malondialdehyde-lysine, an epitope of Ox-LDL, in two groups of LDL receptor-deficient mice for 6 months. One group was fed an atherogenic diet (21% fat and 0.15% cholesterol) that resulted in marked hypercholesterolemia and extensive aortic atherosclerosis; the other group was fed regular rodent chow (4% fat) that did not alter plasma cholesterol levels and induced minimal atherosclerosis. Autoantibody titers significantly increased over time in the group on the atherogenic diet, whereas they remained constant in the chow-fed group. When data from both groups were pooled, a significant correlation was found between the autoantibody titers and the extent of atherosclerosis (r = .61, P < .01). Autoantibody titers also correlated with plasma cholesterol levels (r = .48, P < .05). These results suggest that the rise in autoantibody titers to an epitope of Ox-LDL in this murine model is partially determined by the extent of atherosclerosis but could also be influenced by the degree of hypercholesterolemia or other factors that may influence lipid peroxidation.

Animals↗

PubMed1995

Effect of the antioxidant N,N'-diphenyl 1,4-phenylenediamine (DPPD) on atherosclerosis in apoE-deficient mice.

Apolipoprotein (apo) E-deficient mice develop atherosclerotic lesions that contain epitopes formed during the oxidative modification of lipoproteins, and they demonstrate high titers of circulating autoantibodies against such epitopes, suggesting that this murine strain may provide a model to investigate the atherogenic mechanisms of oxidized lipoproteins (Palinski et al, Arterioscler Thromb. 1994; 14:605-616). To test the hypothesis that lipoprotein oxidation contributes to lesion formation in apoE-deficient mice, we studied the effect of the antioxidant N,N'-diphenyl 1,4-phenylenediamine (DPPD) in mice fed a high-fat diet containing 0.15% cholesterol. Animals were divided into two subgroups matched for sex and plasma cholesterol levels, and DPPD (0.5% wt/wt) was added to the diet of one subgroup. Throughout the 6 months of intervention, DPPD treatment had no significant effect on plasma cholesterol. Plasma levels of DPPD at the end of the experiment were 33.1 mumol/L. As judged by resistance to loss of polyunsaturated fatty acids, lipoproteins (d < 1.019 g/mL) from DPPD-treated animals showed greater resistance to copper-induced oxidation than lipoproteins from control animals. In addition, there was a greater than twofold prolongation of the lag time in the formation of conjugated dienes in the LDL and IDL fractions of DPPD-treated mice. Atherosclerosis was significantly reduced, by 36% in the DPPD-treated mice (14.0 +/- 4.53% of aortic surface area versus 21.9 +/- 11.6%; n = 32; P < .02). These results are consistent with the hypothesis that lipoprotein oxidation contributes to atherogenesis in apoE-deficient mice. However, further studies with other antioxidants are needed to validate this hypothesis.

Animals↗

PubMed1995

Aminoguanidine has both pro-oxidant and antioxidant activity toward LDL.

We previously demonstrated that aminoguanidine (AMGN) was able to prevent oxidative modification of LDL. Initially, we thought that this occurred solely because AMGN trapped reactive breakdown products of lipid peroxidation and prevented apoB modification, similar to AMGN's proposed ability to trap reactive glucose intermediates and prevent advanced glycosylation end-product formation. We now demonstrate that AMGN also displays dose-dependent pro-oxidant and antioxidant activity toward LDL. Moderate doses of AMGN (0.05 to 1.0 mmol/L) prevented lipid peroxidation in LDL exposed to copper. AMGN prevented the loss of polyunsaturated fatty acids and delayed or prevented conjugated-diene formation, both of which are sensitive indicators of lipid peroxidation. The same doses of AMGN also prevented apoB modification, a step distal to lipid peroxidation, as evidenced by the ability to (1) prevent fluorescence at 420 nm, (2) block enhanced electrophoretic mobility, and (3) prevent changes leading to enhanced macrophage uptake. Thus, AMGN inhibits LDL modification both by inhibiting lipid peroxidation as well as by trapping reactive breakdown products of lipid peroxidation. It was also demonstrated that for every LDL, there was also a very low dose of AMGN (about 0.01 mmol/L) that actually promoted lipid oxidation and subsequent protein modification. This activity of AMGN could be enhanced by increasing the content of lipid hydroperoxide in the LDL, eg, by aging or radioiodinating the LDL. Conversely, the pro-oxidant activity could be reduced by pretreatment of LDL with ebselen or vitamin E. We propose a mechanism by which AMGN effects pro-oxidant activity toward LDL at very low concentrations and antioxidant activity at higher concentrations and discuss the practical implications of these observations.

Antioxidants↗

PubMed1995

Immunological evidence for the presence of advanced glycosylation end products in atherosclerotic lesions of euglycemic rabbits.

Atherosclerosis is known to be accelerated in diabetic patients, but the mechanisms of this acceleration are poorly understood. Nonenzymatic glycosylation of long-lived proteins results in the formation of advanced glycosylation end products (AGEs), which are extensively cross-linked and could contribute to atherogenesis. Oxidative modification of LDL is also an important process in atherogenesis. In vitro evidence suggests that hyperglycemia may enhance lipid peroxidation, and conversely, that increased lipid peroxidation may enhance AGE formation. If such interactions occur in vivo, we hypothesized that AGE should be found in atherosclerotic lesions of euglycemic LDL receptor-deficient rabbits in areas rich in lipids and oxidized lipoproteins. To demonstrate the presence of AGEs, we developed antisera against a specific "model" compound of AGE, 2-furoyl-4(5)-(2-furanyl)-1H-imidazole (FFI) by using FFI-hexanoic acid (FFI-HA)-protein adducts as the antigen and against AGEs in general by using AGE-albumin as the antigen. Antisera generated with FFI-HA-protein adducts recognized FFI-HA alone as well as FFI-protein adducts. Native proteins or proteins conjugated with aldehydes formed during lipid peroxidation in vitro were not recognized by these antisera. Immunocytochemistry with both FFI-specific and AGE-specific antisera revealed the presence of these epitopes in atherosclerotic lesions of euglycemic LDL receptor-deficient rabbits but not in normal aortic tissues. AGE epitopes within atherosclerotic lesions were predominantly found in similar locations as epitopes generated during modification of the lipoproteins by oxidation, consistent with the hypothesized interactions between oxidation and glycosylation. Indirect evidence in support of the in vivo presence of FFI-like structures was also obtained by the observation that both diabetic and euglycemic human subjects contained autoantibodies that recognize FFI-protein adducts. Taken together, these data provide immunological evidence for the in vivo presence of FFI-like structures and other AGE-protein adducts in atherosclerotic lesions, even in euglycemic conditions.

Adult↗

PubMed1995

Atherogenesis in transgenic mice with human apolipoprotein B and lipoprotein (a).

The engineering of mice that express a human apoB transgene has resulted in animals with high levels of human-like LDL particles and through crosses with human apo(a) transgenics, high levels of human-like lipoprotein (a) (Lp[a]) particles. In this study, these animals have been used to compare the atherogenic properties of apo(a), LDL, and Lp(a). The presence of the high expressing apoB (apoBH) transgene was associated with a 2.5-fold increase in VLDL-LDL cholesterol (primarily in the LDL fraction) and a 15-fold increase in proximal lesions compared with non-transgenic mice (P < or = 0.0001), while the presence of the low expressing human apoB (apoBL) transgene was not associated with major changes in lipoprotein profiles or increases in aortic lesion size. Examination of aortas of apoBH mice demonstrated lesions along the entire length of the aorta and immunochemical analysis of the lesions revealed features characteristically seen in human lesions including the presence of oxidized lipoproteins, macrophages, and immunoglobulins. Unlike animals with the apoBL transgene, animals with the apo(a) transgene had significant increases in proximal aortic fatty streak lesions compared to nontransgenic control animals (threefold; P < 0.02), while animals with both transgenes, the apo(a)/apo BL double transgenics, had lesions 2.5 times greater than animals expressing the apo(a) transgene alone and eightfold (P < 0.0006) greater than nontransgenic animals. These murine studies demonstrate that marked increases in apoB and LDL resulted in atherosclerotic lesions extending down the aorta which resemble human lesions immunochemically and suggest that apo(a) associated with apoB and lipid may result in a more pro-atherogenic state than when apo(a) is free in plasma.

Animals↗

PubMed1995

Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice.

Murine strains susceptible to atherosclerosis provide valuable models to study factors involved in atherogenesis. In some murine models, limited hypercholesterolemia can be achieved and lesions develop primarily in the aortic origin, in the vicinity of the aortic valve. In other models such as LDL receptor-deficient and apoE-deficient mice, diet-induced or spontaneous hypercholesterolemia and atherogenesis are much greater. To determine whether lesion formation in the aortic origin, where particular pathogenic conditions may exist, correlates with lesion formation throughout the entire aorta, we measured the extent of atherosclerosis in both areas in 8 apoE- and 11 LDL receptor-deficient mice fed cholesterol-rich diets for 3-6 months, as well as in 9 C57BL/6 mice fed an atherogenic diet for a year, using two different morphometric methods. Both apoE-deficient and LDL receptor-deficient mice developed extensive lesions throughout the aorta, and in these models a significant correlation was observed between the extent of lesions in the entire aorta (measured as percent of surface area) and that at the aortic origin (measured as averaged lesion area per cross-section) (r = 0.77, P < 0.0001). In contrast, the plasma cholesterol levels achieved in C57BL/6 mice were much lower, and atherosclerotic lesions were found almost exclusively in the aortic origin. These results demonstrate that in murine models developing extensive aortic lesions, both morphometric methods provide valid and complementary information on the degree and distribution of atherosclerosis, and suggest that under severe atherogenic conditions lesion formation throughout the aorta is determined by the same pathological factors, in each model. Comparison of the extent of atherosclerosis in the entire aorta between genders also showed that male LDL receptor-deficient mice had significantly more lesions than females (29.2 vs. 14.8%, P < 0.005, n = 16). A similar trend was also seen in apoE-deficient mice.

Animals↗

PubMed1994

Pre-eclampsia and serum antibodies to oxidised low-density lipoprotein.

Oxidised low-density lipoprotein (Ox-LDL) has been associated with arterial foam-cell formation, and autoantibodies to Ox-LDL are present in human serum. Lipid peroxidation is enhanced in pre-eclampsia. We assessed whether the titre of IgG autoantibody to an epitope of Ox-LDL, malondialdehyde-conjugated low-density lipoprotein (MDA-LDL), was increased in the sera of pre-eclamptic patients. 16 such patients had significantly higher mean titres of autoantibodies to MDA-LDL than healthy pregnant women (p = 0.028). In a multiple regression model, pre-eclamptic patients still had a significantly higher mean titre (p = 0.048). Enhanced lipid peroxidation may be involved in the foam-cell formation of decidua and in the pathogenesis of pre-eclampsia.

Adult↗

PubMed1994

Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL.

Atherosclerotic lesions contain relatively large quantities of IgG. We have previously shown that both human and rabbit sera contain autoantibodies against epitopes of oxidized (Ox) low-density lipoprotein (LDL) and that LDL isolated from atherosclerotic lesions contains small amounts of tightly bound IgG. However, it is not known whether IgG isolated from atherosclerotic lesions recognizes epitopes present in native LDL or Ox-LDL. IgG was isolated from Watanabe heritable hyperlipidemic (WHHL) rabbit atherosclerotic lesions by sequential salt extractions, purified by fast protein liquid chromatography on protein G, and used in a solid-phase radioimmunoassay. IgG and immune complexes were also isolated from the saline extracts of human lesions by adsorption onto latex beads coated with anti-human IgG antibodies or protein A. IgG isolated from rabbit lesions showed significant titers against malondialdehyde (MDA)-modified LDL and LDL oxidized by copper ions for 4 and 18 hours but not against native LDL. On Western blots, lesion IgG stained MDA-LDL and fragments of Ox-LDL. Western blots of immune complexes isolated from human lesions revealed the presence in the isolated complexes of both apoprotein B and apoprotein B fragments, which reacted with antibodies to MDA-lysine. Furthermore, rabbit lesion IgG immunostained epitopes of Ox-LDL present in human atherosclerotic lesions. Immunostains obtained with rabbit lesion IgG were similar to those obtained with a monoclonal antibody specific for MDA-lysine. The results show that human and rabbit atherosclerotic lesions contain IgG that recognizes epitopes characteristic of Ox-LDL. These data suggest that immunologic processes may be an important component of the atherogenic process.

Adult↗

PubMed1994

ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum.

Apolipoprotein (apo) E-deficient transgenic mice develop marked hyperlipidemia and progressive atherosclerotic lesions. To explore whether oxidative modification of lipoproteins is involved in atherogenesis in this murine model, we performed extensive immunocytochemical studies. Atherosclerotic lesions ranging from early fatty streaks to very advanced plaques were examined from the aortic valve region and the thoracic and abdominal aorta. Using guinea pig antisera against malondialdehyde (MDA)-lysine and 4-hydroxynonenal-lysine, two epitopes generated during the oxidative modification of low-density lipoprotein (LDL), we demonstrated the presence of these "oxidation-specific epitopes" in atherosclerotic lesions. In early lesions, oxidation-specific epitopes were found predominantly in macrophage-rich areas, whereas diffuse extracellular staining predominated in necrotic areas of advanced lesions. We have previously shown that autoantibodies against MDA-lysine are present in the circulation of humans and rabbits and that the immunoglobulin fraction extracted from their lesions contains autoantibodies against several "oxidation-specific" epitopes. Sera from apoE-deficient mice also contained circulating autoantibodies to MDA-lysine, and both early and advanced lesions were rich in murine immunoglobulins. Titers of serum autoantibodies were significantly higher in apoE-deficient mice than in C57BL/6 mice. Autoantibodies in murine plasma recognized MDA-lysine epitopes in atherosclerotic lesions of rabbits, and the immunostaining was competitively inhibited by excess human MDA-LDL. Similar findings were obtained by competitive radioimmunoassay. Finally, a morphometric technique was developed and tested in these mice that allows a quantitative assessment of aortic atherosclerosis. These findings suggest that in apoE-deficient mice, lipoprotein oxidation is involved in atherogenesis and that these transgenic mice constitute an appropriate model with which to study the antiatherogenic effect of antioxidant intervention.

Animals↗

PubMed1993

Abundant expression of apoprotein E by macrophages in human and rabbit atherosclerotic lesions.

Previous studies have demonstrated the presence of apoprotein (apo) E protein and message in arterial lesions. To determine the source of the synthesized apoE, we performed simultaneous in situ hybridization and immunocytochemistry on human and rabbit atherosclerotic tissue. Studies of serial sections of aortic atherosclerotic lesions from humans and hypercholesterolemic New Zealand White rabbits and Watanabe heritable hyperlipidemic rabbits revealed a similar pattern of macrophage-specific apoE expression in the rabbit and human lesions. In early lesions of rabbit atherosclerotic tissue, in which many macrophages were present, there was abundant expression of apoE mRNA. Northern blot analyses of total mRNA obtained from arterial macrophage-derived foam cells, freshly isolated from ballooned, cholesterol-fed New Zealand White rabbits, demonstrated positive hybridization with an apoE-specific riboprobe. Western blot analyses of conditioned media from the isolated foam cells placed in culture for up to 24 hours demonstrated the presence of secreted apoE. These studies demonstrated that in atherosclerotic lesions, arterial wall macrophages synthesize and secrete apoE and probably account for most of the apoE synthesized in the atherosclerotic artery.

Adolescent↗

PubMed1992

Autoantibody against oxidised LDL and progression of carotid atherosclerosis.

Oxidative modification of LDL renders it immunogenic and autoantibodies to epitopes of oxidised LDL, such as malondialdehyde (MDA)-lysine, are found in serum and recognise material in atheromatous tissue. However, there has been no prospective study to assess the importance of oxidised LDL among patients with vascular disease. We compared the titre of autoantibodies to MDA-modified LDL and native LDL in baseline serum samples of 30 eastern Finnish men with accelerated two-year progression of carotid atherosclerosis and 30 age-matched controls without progression. Neither group had specific antibody binding to native LDL. A titre was defined as a ratio of antibody binding to MDA-LDL/binding to native LDL. Cases had a significantly higher titre to MDA-LDL (2.67 vs 2.06, p = 0.003). Cases also had a greater proportion of smokers (37% vs 3%), higher LDL cholesterol (4.2 mmol/l vs 3.6 mmol/l), and higher serum copper concentration (1.14 mg/l vs 1.04 mg/l). Even after adjusting for these variables and the severity of baseline atherosclerosis, the difference in antibody titre remained significant in a multifactorial logistic model (p = 0.031). Thus, the titre of autoantibodies to MDA-LDL was an independent predictor of the progression of carotid atherosclerosis in these Finnish men. Our data provide further support for a role of oxidatively modified LDL in atherogenesis.

Adult↗

PubMed1991

Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts.

Pure macrophage-derived foam cells (MFC) were isolated from the aortas of rabbits made atherosclerotic by balloon deendothelialization followed by diet-induced hypercholesterolemia. The MFC were isolated under sterile conditions using an enzymatic digestion procedure and discontinuous density gradient centrifugation. The purity of the MFC preparations was verified immunocytochemically with the macrophage specific monoclonal antibody RAM-11. MFC plated in medium containing 0.5% FCS for 24 h contained approximately 600 micrograms cholesterol per mg cell protein, 80% of which was esterified cholesterol. The MFC specifically degraded low density lipoprotein (LDL), acetyl-LDL, copper oxidized LDL, and beta-very low density lipoprotein (beta-VLDL) at rates comparable to mouse peritoneal macrophages (MPM) in 5-h assays. MFC within sections of the atherosclerotic lesions from the ballooned rabbits as well as the MFC isolated from the same lesions in the presence of antioxidants, exhibited positive immunoreactivity with polyclonal guinea pig antisera and mouse monoclonal antibodies directed against malondialdehyde-LDL, and 4-hydroxynonal-LDL. The MFC also exhibited the capacity to induce the oxidation of LDL at rates comparable to those exhibited by MPM and rabbit aortic endothelial cells. These data provide direct evidence that arterial wall macrophages express modified LDL receptors in vivo, contain epitopes found in oxidized-LDL and are capable of oxidizing LDL even when maximally loaded with cholesterol.

Animals↗

PubMed1991

Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy.

Capillary occlusions are characteristic features of the early diabetic retinopathy and are presumed to initiate neovascularization. Activated leukocytes can cause microvascular occlusions and cell damage by release of cytotoxic products. To explore the role of leukocytes in capillary occlusion, nonperfusion, and neovascularization of diabetic retinopathy, a rat model was used, in which a diabetic state was induced by alloxan. Retina flat preparations were differentially stained for monocytes and granulocytes. Capillary occlusion, nonperfusion, and neovascularization were assessed microscopically in the center, midperiphery, and periphery of the retina. In contrast to control retinas, 2- to 9-month diabetic rats showed many capillary occlusions by leukocytes, especially monocytes, endothelial cell damage, extravascular macrophage accumulation, and tissue damage. The percentage of activated monocytes and granulocytes in the circulating blood of diabetic rats was greatly increased, and areas of capillary 'loss' and neovascularization in the retina coincided with sites of extravascular leukocytes. The authors' results suggest a potential role of monocytes and macrophages in the pathogenesis of diabetic retinopathy.

Alloxan↗

PubMed1990

Lipoproteins in normal and atherosclerotic aorta.

Each method used for the extraction and isolation of intimal lipoproteins has advantages and disadvantages. Gentle extraction methods are needed to characterize subtle modifications in the structure and biologic properties of the lipoproteins, whereas more aggressive methods are needed if the goal is to maximize the yield of lipoproteins from atherosclerotic arteries. The present paper evaluates different methods used for the isolation of intimal lipoproteins. Normal intima contains remnant-like and low density lipoprotein (LDL)-like particles that more strongly stimulate cholesterol esterification in macrophages than do control plasma LDL. Both fractions contain apolipoprotein (apo) E but neither shows clear signs of oxidative modification. LDL-like particles from atherosclerotic lesions, on the other hand, contain malondialdehyde- and 4-hydroxynonenal-lysine adducts in apo B, are chemotactic for monocytes and show increased degradation in macrophages, a process that oxidized LDL prepared in vitro can compete with. The findings support the conclusion that at least a portion of the LDL isolated from atherosclerotic lesions is similar, if not identical, to oxidatively modified LDL.

Animals↗

PubMed1990

Macrophages, endothelial cells, and lipoprotein oxidation in the pathogenesis of atherosclerosis.

One of the earliest phenomena in the atherogenic process in cholesterol-fed rabbits appears to be the trapping of low density lipoproteins (LDL) at lesion-prone sites in the aorta. The resulting increase in residence time may facilitate oxidation of the lipoproteins, which, in turn, may be a chemotactic signal for monocytes to enter the intima. Oxidized lipoproteins may also be the major source of the cholesterol that the cells accumulate during their transformation into macrophage-derived foam cells (MFC). Adherent monocytes appear to cluster over small groups of subendothelial foam cells, perhaps in response to the enhanced expression of specific adhesion molecules on the surface of endothelial cells and/or monocytes following activation by oxidized lipoproteins. Lipoproteins oxidized by MFC may also injure endothelial cells causing them to retract or rupture. The resulting exposure of the MFC facilitates the formation of mural thrombi. MFC contain oxidation-specific lipid-protein adducts and specifically express the mRNA for 15-lipoxygenase, an enzyme potentially involved in lipoprotein oxidation. MFC isolated from atherosclerotic lesions and containing up to 600 micrograms cholesterol/mg protein are still capable of binding and degrading modified lipoproteins and affecting the oxidation of LDL.

Animals↗

PubMed1989

Low density lipoprotein undergoes oxidative modification in vivo.

It has been proposed that low density lipoprotein (LDL) must undergo oxidative modification before it can give rise to foam cells, the key component of the fatty streak lesion of atherosclerosis. Oxidation of LDL probably generates a broad spectrum of conjugates between fragments of oxidized fatty acids and apolipoprotein B. We now present three mutually supportive lines of evidence for oxidation of LDL in vivo: (i) Antibodies against oxidized LDL, malondialdehyde-lysine, or 4-hydroxynonenal-lysine recognize materials in the atherosclerotic lesions of LDL receptor-deficient rabbits; (ii) LDL gently extracted from lesions of these rabbits is recognized by an antiserum against malondialdehyde-conjugated LDL; (iii) autoantibodies against malondialdehyde-LDL (titers from 512 to greater than 4096) can be demonstrated in rabbit and human sera.

Alkaline Phosphatase↗

PubMed1989

Increased microvascular resistance to blood flow in the rat hindlimb after perfusion with neuraminidase.

1. The ability of blood to flow through capillaries with diameters smaller than that of erythrocytes and leucocytes has been explained hypothetically on the basis of electrostatic repulsion between vessel walls and circulating cells, but in the absence of in vivo evidence. Following our discovery of extraordinarily high densities of sialic acids on endothelial surfaces, we have now devised experiments to determine to what extent microcirculatory blood flow might depend on these negative charges. 2. Hindlimbs of rats anaesthetized with ether and pentobarbitone were perfused through the femoral artery at constant volume with continuous recording of inflow resistance: first with carotid arterial blood containing continually infused acetylcholine at concentrations which minimized peripheral resistance without affecting heart rate; then for 5 min with buffered saline containing acetylcholine at the same concentration plus neuraminidase (from Vibrio cholerae, at 0.1 mg/ml) to remove endothelial sialic acids (for control experiments without neuraminidase); and then again with acetylcholine-infused carotid blood. 3. As a consequence of the saline perfusion, there was a rapid initial rise and fall of inflow resistance. The subsequent changes in resistance were calculated as the difference between its lowest value in the first 10 min and the value after 60 min. Controls and neuraminidase-perfused groups were compared using the t test for unpaired measurements. 4. In four control experiments inflow resistance decreased by 10-40% (14 +/- 10%, mean +/- S.E.M.). In three experiments with neuraminidase, inflow resistance increased by 24-38% (29 +/- 4%, mean +/- S.E.M.). The difference between the saline and the neuraminidase-perfused groups was significant (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1989

Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man.

Three lines of evidence are presented that low density lipoproteins gently extracted from human and rabbit atherosclerotic lesions (lesion LDL) greatly resembles LDL that has been oxidatively modified in vitro. First, lesion LDL showed many of the physical and chemical properties of oxidized LDL, properties that differ from those of plasma LDL: higher electrophoretic mobility, a higher density, higher free cholesterol content, and a higher proportion of sphingomyelin and lysophosphatidylcholine in the phospholipid fraction. A number of lower molecular weight fragments of apo B were found in lesion LDL, similar to in vitro oxidized LDL. Second, both the intact apo B and some of the apo B fragments of lesion LDL reacted in Western blots with antisera that recognize malondialdehyde-conjugated lysine and 4-hydroxynonenal lysine adducts, both of which are found in oxidized LDL; plasma LDL and LDL from normal human intima showed no such reactivity. Third, lesion LDL shared biological properties with oxidized LDL: compared with plasma LDL, lesion LDL produced much greater stimulation of cholesterol esterification and was degraded more rapidly by macrophages. Degradation of radiolabeled lesion LDL was competitively inhibited by unlabeled lesion LDL, by LDL oxidized with copper, by polyinosinic acid and by malondialdehyde-LDL, but not by native LDL, indicating uptake by the scavenger receptor(s). Finally, lesion LDL (but not normal intimal LDL or plasma LDL) was chemotactic for monocytes, as is oxidized LDL. These studies provide strong evidence that atherosclerotic lesions, both in man and in rabbit, contain oxidatively modified LDL.

Adult↗