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Biomedical subjects

J Regnström

Publications and source records attributed to J Regnström.

At least 19 recordsLinked to original sources
PubMed1999

Serum urate determines antioxidant capacity in middle-aged men - a controlled, randomized diet and exercise intervention study.

OBJECTIVES: To study whether advice on diet and/or exercise, given in order to reduce cardiovascular risk factors in middle-aged men, affects the intake of antioxidants, urate concentration and the total antioxidant capacity in serum. DESIGN: A 6-month randomized controlled intervention study. SETTING: Primary Health Care in Sollentuna, Stockholm, and the Department of Medicine, Karolinska Hospital, Stockholm, Sweden. SUBJECTS: One hundred and fifty-eight healthy men (46.2 +/- 5.0 years) with moderately raised cardiovascular risk factors. INTERVENTIONS: Advice on diet (D, n = 40), exercise (E, n = 39), diet and exercise (DE, n = 39) and a control group (C, n = 39). MAIN OUTCOME MEASURES: Dietary intake, exercise habits, S-urate and the antioxidant capacity in serum (TAOC). RESULTS: After 6 months, changes in dietary and exercise habits were seen in all three intervention groups and favourable effects were seen on BMI, waist circumference, blood pressure, S-cholesterol and fasting insulin. The intake of alpha-tocopherol was decreased in groups D and E (P < 0.01) and beta-carotene was increased in groups D and DE (P < 0.01). In group DE, the intake of vitamin C was increased (P < 0.05). S-urate was reduced in group D from 345 to 325 micromol L-1 (P < 0.05). No significant changes in TAOC were seen in any group. S-urate and TAOC were correlated (r = 0. 58, P < 0.001) and S-urate was correlated to several parameters in the metabolic syndrome. CONCLUSION: Favourable changes in diet and exercise reduced several cardiovascular risk factors but did not affect the total antioxidant capacity in serum. S-urate was a strong determinant of the antioxidant capacity.

Adult↗
PubMed1998

Helicobacter pylori seropositivity is not associated with inflammatory parameters, lipid concentrations and degree of coronary artery disease.

OBJECTIVES: To determine the prevalence of chronic infection with Helicobacter pylori (HP) in patients with established coronary artery disease (CAD) and in healthy controls. Furthermore, to investigate whether HP infection is associated with inflammatory parameters, lipid concentrations and degree and progression of CAD. DESIGN: A case-control study combined with a prospective angiographic study. SETTING: Stockholm Metropolitan Area, Sweden. PATIENTS AND METHODS: A material consisting of 92 young men aged 40.9 +/- 3.2 (mean +/- SD) years, with previous myocardial infarction and documented coronary atherosclerosis, and 95 healthy sex-matched controls, aged 43.2 +/- 3.0 (mean +/- SD) years, with similar socio-economic status and ethnic background was analysed for the prevalence of HP seropositivity, plasma concentrations of the inflammatory parameters fibrinogen, tumour necrosis factor alpha and orosomucoid, and serum concentrations of lipids. The impact of HP seropositivity on degree and progression of CAD, as assessed by quantitative coronary angiography, was also determined. RESULTS: The study population of mainly Scandinavian origin had a low prevalence of HP seropositivity in comparison with previously published European populations. No significant increase in HP seropositivity was found in patients compared with controls (42.2 vs. 32.6%). Furthermore, HP infection was not associated with increased levels of inflammatory parameters, lipid concentrations or with degree of angiographically determined CAD at baseline, or progression of CAD and clinical events over 5 years. CONCLUSIONS: HP infection is not associated with inflammatory parameters and lipid concentrations and could not be confirmed as a risk factor for CAD.

Adult↗
PubMed1998

An animal model to study local oxidation of LDL and its biological effects in the arterial wall.

Oxidized LDL (oxLDL) is present in atherosclerotic lesions and is believed to play a key role in atherogenesis. Mainly on the basis of cell culture studies, oxLDL has been shown to produce many biological effects that influence the atherosclerotic process. To study LDL oxidation in vivo, we have established a model in which Sprague-Dawley rats are given a single injection of unmodified human LDL (> or = 4 mg/kg body weight). Within 6 hours, an accumulation of apolipoprotein B and epitopes present on oxLDL are detected in the arterial endothelium and media. The presence of oxLDL is associated with activation of the transcription factor nuclear factor-kappaB in the endothelium as well as endothelial expression of intercellular adhesion molecule-1. Injection of LDL enriched with the antioxidant probucol resulted in arterial accumulation of apolipoprotein B, but the expression of oxLDL-specific epitopes was reduced at 24 hours. Thus, this simple model has the potential to analyze the mechanisms behind and biological effects of LDL oxidation in vivo.

Adult↗
PubMed1998

Role of caveolae in cholesterol transport in arterial smooth muscle cells exposed to lipoproteins in vitro and in vivo.

Arterial smooth muscle cells are able to shift between two major differentiated states with distinct morphologic and functional properties, a contractile phenotype and a synthetic phenotype. Recently, it was demonstrated that contractile smooth muscle cells have numerous caveolae and that these specialized regions of the plasma membrane, to a large extent, are lost when the cells are modified into a synthetic phenotype. At the same time, the levels of the cholesterol-binding membrane protein caveolin remained unchanged and caveolin was redistributed from the cell surface to the perinuclear cytoplasm. In the present investigation, electron microscopy was used to study how smooth muscle cells of different phenotypes react to exposure to low-density lipoprotein and other lipoproteins both in vitro and in vivo. Our findings indicate that contractile cells (present early in primary culture and in the media of normal arterial walls) do not accumulate lipids in the cytoplasm and release excess cholesterol by means of plasma membrane caveolae. Extracellularly, the expelled lipids were built into membranous configurations and piled up as myelin-like deposits. In synthetic cells (formed after a few days in primary culture and as a response to arterial injury), lipids gathered in cytoplasmic droplets and increased amounts of membranous inclusions appeared in endosomes and lysosomes. On the other hand, no signs of extracellular discharge of lipids were detected. The results suggest that contractile smooth muscle cells use caveolin and caveolae to free themselves of excess lipoprotein-derived cholesterol and so manage to maintain a balance in the influx and efflux of cholesterol. Synthetic smooth muscle cells show a Golgi-like immunostaining for caveolin but have an insufficient capacity to use this protein to transport cholesterol to the plasma membrane and out of the cell. Cholesterol will then rather be esterified and collect in lipid droplets, eventually leading to foam cell formation if the uptake of lipoprotein continues.

Animals↗
PubMed1997

Tumor necrosis factor-alpha activates smooth muscle cell migration in culture and is expressed in the balloon-injured rat aorta.

In experimental models of atherosclerosis, activation of smooth muscle cell (SMC) migration from the media to the intima is preceded by intimal accumulation of inflammatory cells, suggesting that cytokines may be involved in this process. The present study demonstrates that tumor necrosis factor-alpha (TNF-alpha) regulates cytoskeletal organization of SMCs by inducing depolymerization of actin stress fibers and dispersion of vinculin from sites of focal adhesion and stimulates the migration of cultured human SMCs in a dose-dependent manner. Moreover, TNF-alpha induces rapid activation of the c-ets-1 gene, which codes a transcription factor known to regulate enzymes important for matrix degradation during cell migration. Balloon catheter injury of the rat femoral artery resulted in medial expression of TNF-alpha within 6 hours. This expression appeared to be localized to SMCs and remained elevated until SMCs began to migrate into the intima 7 days after injury. These findings demonstrate that TNF-alpha has a stimulatory effect on SMC migration and suggest that TNF-alpha may be involved in the intimal recruitment of SMCs during plaque formation.

Animals↗
PubMed1996

The effect of probucol on low density lipoprotein oxidation and femoral atherosclerosis.

The Probucol Quantitative Regression Swedish Trial (PQRST) investigated the effect of the lipid lowering and antioxidant drug probucol on the development of atherosclerosis in humans. 303 hypercholesterolemic patients were randomized to receive either probucol or placebo, in combination with dietary advice and cholestyramine for a three-year period. Probucol was not found to effect progression regression of femoral atherosclerosis significantly as assessed by quantitative arteriography. To evaluate the effectiveness of probucol as an antioxidant during the study period, detailed analyses were performed on 42 of the randomized patients. During the trial, probucol-treated patients (n = 26) had 15% lower total cholesterol (P < 0.01) and 35% lower high density lipoprotein (HDL) cholesterol (P < 0.0001) compared with controls (n = 16). Low density lipoprotein (LDL) from probucol treated individuals was more resistant to oxidation by Cu2+ as determined by the lag phase for the formation of conjugated dienes (220 +/- 8 vs. 82 +/- 7 min (mean +/- S.E)), showed a 13 times lower formation of lipid peroxides, a 97% reduction in macrophage degradation and close to 90% less decrease in LDL receptor binding following oxidation as compared with controls (P < 0.001 for all differences). The results demonstrate that although probucol provided a significant protection against Cu(2+)-induced oxidative modification of LDL, it lacked effect on the development of femoral atherosclerosis. The relevance of these observations for the proposed role of lipid oxidation in atherosclerosis is discussed.

Adult↗
PubMed1996

Inverse relation between the concentration of low-density-lipoprotein vitamin E and severity of coronary artery disease.

Oxidation of low-density lipoprotein (LDL) is believed to play an important role in atherogenesis, and antioxidant vitamins are thought to protect against coronary artery disease (CAD). We investigated whether the vitamin E concentrations in serum and LDL were associated with the severity of CAD as assessed by a semiquantitative scoring system in which coronary angiograms are analyzed for the number and size of distinct stenotic lesions (global stenosis score). The study group consisted of 64 consecutive male survivors of myocardial infarction aged < 45 y. Lipid-adjusted serum and LDL vitamin E concentrations were significantly lower in the patients than in 35 age-matched male control subjects, whereas the absolute serum and LDL vitamin E concentrations did not differ significantly. No associations were found between the serum concentration or lipid-adjusted serum values of vitamin E and the stenosis score. In contrast, significant inverse correlation was found between the LDL vitamin E concentration, whether adjusted to the lipid (r=-0.477,P<0.001) or protein (r=-0.375, P<0.01) content of LDL, and the global coronary stenosis score. We conclude that a low LDL vitamin E concentration might play a role in the development of stenoses in coronary arteries and may contribute to clinically manifest CAD.

Adult↗
PubMed1996

Active oxygen species and lysophosphatidylcholine are involved in oxidized low density lipoprotein activation of smooth muscle cell DNA synthesis.

It has recently been shown that oxidative modification of LDL enhances the mitogenic effect of LDL on smooth muscle cell (SMC) DNA synthesis. However, because of its complex chemical structure, the mitogenic components have not been well characterized. Exposure of LDL to the oxidant Cu2+ is followed by a rapid accumulation of peroxides that peaks after 8 to 12 hours and a conversion of the phospholipid phosphatidylcholine into lysophosphatidylcholine that continues for up to 48 hours. Most of the mitogenic activity is formed during the first 4 hours of oxidation. Both superoxide dismutase and catalase effectively inhibit the mitogenic activity of oxidized LDL, suggesting involvement of reactive oxygen intermediates. In the presence of 1% serum, low concentrations of hydrogen peroxide activated SMC DNA synthesis in a dose-dependent manner, with a maximal effect at a concentration of 200 mumol/L, whereas higher concentrations were inhibitory. Lysophosphatidylcholine also enhanced SMC DNA synthesis, with a maximal stimulation at a concentration of 10 mumol/L. Oxysterols, which also accumulate in oxidized LDL, effectively inhibited DNA synthesis. These results demonstrate that oxidation of LDL is associated with formation of several substances affecting the growth of SMCs. Among these substances, low levels of reactive oxygen intermediates and lysophosphatidylcholine stimulate DNA synthesis, whereas at a higher concentration they, as well as oxysterols, are inhibitory.

Cells, Cultured↗
PubMed1996

Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits.

Although the existence of an immune response against modified lipoproteins in atherosclerosis has been observed in experimental animals as well as in humans, the precise pathophysiological relevance of these findings remains unclear. In this study we determined the effect of an immunization with homologous LDL and copper-oxidized LDL on the formation of atherosclerotic plaque in hypercholesterolemic rabbits. Immunizations were performed at the start of a cholesterol-rich diet and 3 weeks later. After 16 weeks, antibodies against oxidized LDL had developed in rabbits given hypercholesterolemic diet alone, but the titers were increased by twofold in rabbits immunized with oxidized LDL as well as in rabbits immunized with LDL, suggesting that the LDL had also become oxidized during the preparation and/or immunization procedure. Immunization with LDL and oxidized LDL reduced atherosclerotic lesions in the proximal aorta by 74% (P < .05) and 48% (P = NS), respectively. The cellular composition of the lesions was not affected by the immunizations. These results support the hypothesis that an immune response against modified LDL has a protective effect against the development of early atherosclerotic lesions.

Animals↗
PubMed1996

A decrease in cardiovascular risk factors in healthy 40-year-old Swedish men between 1980-1983 and 1991-1992.

BACKGROUND: Cardiovascular risk factors were compared between two samples of urban middle-aged healthy men investigated in 1980-1983 (n = 106) and 1991-1992 (n = 118), respectively. METHODS: All subjects, who served as controls in an ongoing study on mechanisms behind myocardial infarction, were randomly selected from a register that contains all the inhabitants (1.65 million) in the Stockholm Metropolitan Area. The study programme included recordings of weight, height, smoking habits, blood pressure and blood sampling. Blood and lipoprotein lipid levels, glucose concentrations before and during an oral glucose tolerance test and fibrinogen levels were determined. RESULTS: The 1991-1992 sample had lower systolic blood pressure and lower concentrations of total blood cholesterol, fasting blood glucose and fibrinogen than the 1980-1983 sample. The lower total blood cholesterol level in the 1991-1992 sample was due to a decrease in low- and high-density lipoprotein cholesterol concentrations. In addition, a tendency was seen towards a decrease in prevalence of smoking in the latter sample. No differences were noted in body mass index, diastolic blood pressure, oral glucose tolerance or total triglycerides between the two samples.

Adult↗
PubMed1995

Cellular processing of apolipoprotein B-containing lipoproteins from young post-infarction patients and healthy controls.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was measured in fibroblasts incubated with large (Sf > 60) and small (Sf 20-60) very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles, at similar protein concentrations, from young post-infarction patients and healthy controls. The results showed that apolipoprotein (apo) B-containing lipoproteins (VLDL, IDL, LDL) from patients suppressed HMG-CoA reductase activity to a similar extent compared to apo B-containing lipoproteins from controls. When all subjects taken together were grouped according to triglyceride levels, it was found that small VLDL from hypertriglyceridaemic individuals suppressed the HMG-CoA reductase activity more than small VLDL from normotriglyceridaemic individuals. The opposite pattern was seen for LDL. The lipoprotein composition was related to the respective HMG-CoA reductase activity. In addition to a positive association between the cholesterol content of small VLDL and LDL, and the inhibition of HMG-CoA reductase activity, the apo C I and C II content of small VLDL and IDL was inversely related to the suppression of HMG-CoA reductase activity. This study shows that the cellular processing of apo B-containing lipoproteins in young post-infarction patients and healthy controls is heterogeneous and dependent on the composition of the lipoprotein.

Adult↗
PubMed1995

The susceptibility of low density lipoprotein to chemical oxidation is closely related to proneness to biological modification.

U937 is a monocytic cell line dependent on low density lipoprotein (LDL) receptor-mediated uptake of cholesterol for proliferation. However, exposure of U937 cells to LDL also results in an oxidative modification of LDL. We report here that the oxidative modification of LDL by U937 cells results in inhibition of growth and cell death. This finding suggests that analysis of U937 cell growth in presence of LDL may be used to determine the susceptibility of LDL to biological oxidative modification. There was an inverse association between the effect of LDL on U937 cell growth and the rate of degradation of U937 cell-modified LDL in mouse peritoneal macrophages (r = -0.82, p < 0.05) suggesting a coupling between proneness of LDL to develop cytotoxicity and affinity for scavenger receptors. In a group of young post-infarction patients (n = 18) the susceptibility of LDL to chemical oxidation as determined by analysis of the lag phase for formation of conjugated diens in presence of copper ions was compared with the biological modification of LDL as assessed by analysis of U937 cell growth in presence of LDL. The results demonstrated a close relation between the estimates of chemical oxidation and biological modification (r = 0.86, p < 0.005) suggesting that LDL, which is prone to become oxidised by copper also is more prone to become modified by cells in vivo.

Animals↗
PubMed1994

Influence of lipoprotein lipids, dietary fat and smoking on macrophage degradation of native and oxidized low density lipoprotein.

Relatively little is known about the biological mechanisms by which lipoproteins promote atherogenesis. It has, however, been shown that structural modification of low density lipoprotein (LDL), such as by oxidation, results in their uptake and degradation by intimal macrophages and consequently leads to formation of lipid-rich atherosclerotic lesions. The aim of the present investigation was to study the influence of dietary intake of fat, lipoprotein lipid composition, smoking and gender on macrophage degradation of LDL before and after oxidation. The study group consisted of 48 males and 56 females with hyperlipidemia taking part in the open prerandomization phase of the Probucol Quantitative Regression Swedish Trial (PQRST). Analysis including lipoprotein determinations, dietary and smoking habit interviews, LDL degradation by macrophages, LDL receptor binding and LDL thiobarbituric acid reactive substance (TBARS) levels before and after copper ion-induced oxidation was done during the pre-andomization phase of the study. Increased plasma and very low density lipoprotein (VLDL) triglyceride levels were associated with an increased macrophage degradation of native LDL, whereas no such association was found after oxidation of LDL. The dietary intake of polyunsaturated fatty acids (PUFA) was also inversely related to the degradation of native LDL by macrophages, but increased the rate at which oxidized LDL was degraded. Smoking and gender did not influence the rate of macrophage degradation of native or oxidized LDL. It is concluded that hypertriglyceridemia is associated with an increased macrophage degradation of LDL. This may represent a mechanism by which hypertriglyceridemia promotes atherosclerosis.

Adult↗
PubMed1993

The role of lipids and antioxidative factors for development of atherosclerosis. The Probucol Quantitative Regression Swedish Trial (PQRST).

The effect of probucol on the development of atherosclerosis is being investigated in the Probucol Quantitative Regression Swedish Trial (PQRST). Hypercholesterolemic patients are randomized to receive either probucol 0.5 g twice daily or placebo in a double-blind manner, in combination with dietary therapy and cholestyramine 8-16 g daily for a 3-year period. The primary endpoint of the trial is the change in atheroma volume, assessed by annual quantitative angiography involving 20-cm segments of the femoral artery. Data from the open diet and prerandomization phase indicate that probucol added to dietary intervention plus cholestyramine produced highly significant reductions in total (-17%), low-density lipoprotein (LDL; -10%), and high-density lipoprotein (-30%) cholesterol. From a subpopulation, LDL levels were isolated during different stages of the prerandomization phase. LDL was exposed to the oxidant Cu2+ and binding to fibroblasts as well as degradation by macrophages was measured. The generation of thiobarbituric acid-reactive substances (TBARS) was also measured. Probucol prevented degradation of copper-exposed LDL by macrophages and also reduced the formation of TBARS, indicating that probucol protected LDL from oxidation. After the trial concludes in December 1992, statistical models will be used to investigate how much of the change in atherosclerosis is explained by changes in lipoprotein concentrations and how much is explained by probucol's antioxidative effects. Thus, other metabolic factors such as dietary intake and circulating levels of lipid soluble vitamins and fatty acids that may modify the possible antioxidative effects of probucol are also measured and will be related to change in atherosclerosis.

Aged↗
PubMed1993

Analysis of lipoprotein diene formation in human serum exposed to copper.

The susceptibility of low density lipoprotein (LDL) to oxidative modification can be determined by analyzing the lag phase for initiation of diene formation in isolated LDL exposed to Cu2+. However, the applicability of this assay for clinical studies is limited by the requirement of a preparative ultracentrifugation of LDL and that the influence of water soluble antioxidants and other lipoproteins is not accounted for. The present paper describes a modification of this assay allowing determination of lag phase for lipoprotein diene formation in serum. The formation of dienes in serum exposed to Cu2+ begins following the consumption of serum alpha-tocopherol, correlates to the formation of thiobarbituric acid reactive substances (r = 0.987, n = 8), is inhibited by the addition of ascorbic acid and is absent in lipoprotein-deficient serum. It is also accompanied by an increased mobility of serum lipoproteins on agarose gel electrophoresis and with an ability of serum to displace isolated copper-oxidized LDL from binding sites mediating degradation in mouse peritoneal macrophages. The coefficient of variance of the analysis is below 3%. It is concluded that this technique allows analysis of lipoprotein oxidation susceptibility in serum samples and may prove to be useful in clinical analysis of the lipoprotein oxidation susceptibility.

Animals↗