There are limited data on the effects of statins on serum vitamin E status in dyslipidaemic patients, and no comparisons between statins have been published previously. We have investigated the effect of Atorvastatin and Simvastatin on serum vitamin E status in dyslipidaemic patients. A total of 20 dyslipidaemic patients (14 males, 6 females, mean age 49.15±3.28 years), previously not treated with a lipid lowering agent, were recruited into the study. These patients were randomized to treatment group and received either: Simvastatin 10mg/day (n = 11) or Atorvastatin 10mg/day (n = 9) for 4 months. The control group comprised 14 patients from the same clinic, who were given lifestyle advice, but whose drug treatment remained unchanged for the duration of the study. Serum concentrations of vitamin E, high sensitivity C-reactive protein (hs-CRP) and fasted lipid profiles preand post-treatment were measured in all subjects. There were the expected significant reductions in serum lipids in the patients treated with either statin (P<0.001). Overall statin treatment was also associated with a significant reduction in serum vitamin E (21%, P<0.001) and hsCRP (45%, P<0.05). There was no significant change in these parameters in the control patients. The serum vitamin E / total cholesterol ratio was not significantly altered in patients receiving Atorvastatin, or Simvastatin despite the significant reduction in serum vitamin E. No change in vitamin E status was observed in the controls.

We have previously shown that antibody titres to several heat-shock proteins (Hsps) are elevated in dyslipidaemic patients and subjects with established vascular disease. Obesity is known to be associated with raised serum inflammatory markers suggesting a state of heightened immune activation. Hence, we have investigated the association between indices of obesity and several Hsp antibody titres in healthy subjects. Subjects ( n =170) were recruited from among employees at the University of Surrey and the Royal Surrey County Hospital, Guildford, UK. Of these subjects, 35 were obese with a body mass index (BMI)⩾30 kg/m 2 (19 male and 16 female subjects), 58 were overweight with 30>BMI⩾25 kg/m 2 (36 male and 22 female subjects) and 77 were of a normal weight with BMI<25 kg/m 2 (31 male and 46 female subjects). Overall, obese subjects had significantly higher plasma anti-Hsp-60 ( P <0.001), anti-Hsp-65 ( P <0.05) and anti-Hsp-70 ( P <0.05) compared with overweight and normal weight subjects.

The epidermal growth factor receptor is a member of type-I growth factor receptor family with tyrosine kinase activity that is activated following the binding of multiple cognate ligands. Several members of the EGF family of ligands are expressed by cells involved in atherogenesis. EGF receptor mediated processes have been well characterised within epithelial, smooth muscle and tumour cell lines in vitro, and the EGF receptor has been identified immunocytochemically on intimal smooth muscle cells within atherosclerotic plaques. There is also limited evidence for the expression of the EGF receptor family on leukocytes, although their function has yet to be clarified. In this review, we will discuss the biological functions of this receptor and its ligands and their potential to modulate the function of cells involved in the atherosclerotic process.

Antibody titers to heat shock protein (Hsp)-60 and -65 are positively related to risk of vascular disease and cardiovascular endpoints. There are few data on the factors that regulate the levels of these antibodies. It is known that the statins have antiinflammatory and immunoregulatory properties. The authors examined the effects of 2 statins, simvastatin (Zocor ® ) and atorvastatin (Lipitor ® ) on antibody titers to Hsp-60, -65, and -70 in a group of dyslipidemic patients. Twenty patients attending a lipid clinic, and previously not receiving lipid-lowering treatment, were treated with 10 mg of simvastatin (n=11) or atorvastatin (n=9) for 4 months. An additional 14 patients were recruited from the same clinic at the same hospital as a control group. The medication of these latter patients was unaltered for 4 months and the same parameters were measured as for the statin group. Antibody titers to Hsp-60, -65, and -70 were measured by enzyme-linked immunosorbent assay and lipoprotein profile and highly sensitive serum C-reactive protein (CRP) were measured by routine methods before and after treatment. Pretreatment and posttreatment data were compared by paired t or Mann-Whitney tests. Overall statin treatment was associated with a significant reduction in median antibody titers to Hsp-60 (17.2%, p=0.03), Hsp-65 (15.9%, p=0.003) and Hsp-70 (8.3%, p=0.006), but not in control patients. Both statins caused a reduction in median serum CRP concentrations (45% overall, p<0.05), but significant changes were not observed in the control patients. The effects on Hsp antibody titers were not related to changes in serum CRP concentrations (p>0.05). However, there was a significant correlation between changes in antibody titers to Hsp-60 vs Hsp-65 (p<0.01), Hsp-60 vs Hsp-70 (p<0.05), and Hsp-65 vs Hsp-70 (p<0.001). Statin treatment was associated with a reduction in antibody titers to Hsp-60, -65, and -70. This reduction is not fully explained by the antiinflammatory effects of the statins but may be due to their other immunomodulatory properties.

BACKGROUNDThe heat shock proteins (HSPs) are protein chaperones. Higher titers of antibody to HSPs (anti-HSPs) have been reported in atherosclerosis, which may contribute to immunoactivation in this process.OBJECTIVEWe investigated whether dietary antioxidants and fat intake are associated with changes in anti-HSP titers in dyslipidemic subjects.DESIGNPatients (n = 238) were recruited from hospital lipid clinics. Control subjects (n = 188) were recruited from university and hospital employees. Food-frequency questionnaires were used to estimate dietary antioxidants and fat.RESULTSDyslipidemic patients had significantly higher titers of anti-HSPs than did control subjects; expressed in medians and interquartile ranges of absorbance units, anti-HSP-60 titers were 0.27 (0.18-0.37) and 0.22 (0.16-0.30), anti-HSP-65 titers were 0.45 (0.28-0.79) and 0.31 (0.22-0.50), and anti-HSP-70 titers were 0.22 (0.17-0.30) and 0.19 (0.13-0.27), respectively. Median and interquartile ranges of serum concentrations of C-reactive protein [1.25 (0.42-3.26) and 0.58 (0.17-1.42)] and mean (+/-SEM) concentrations of vitamin E (16.36 +/- 0.31 and 14.08 +/- 0.38) were also significantly higher in patients than in control subjects, respectively. In dyslipidemic patients, the major dietary predictors of the variability in anti-HSP-60 titers were vitamin C (P = 0.005), vitamin E (P = 0.04), and total fat (P = 0.009) intakes; for anti-HSP-65 titers, vitamin C was the major predictor (P = 0.002). These findings remained significant after adjustment for confounding factors.CONCLUSIONSAnti-HSP-60, -65, and -70 titers are significantly higher in dyslipidemic patients with or without established coronary disease. Our data indicate an association between dietary constituents and the immune response to HSPs in dyslipidemic subjects.

Patients previously not treated with a lipid-lowering agent (n=20; mean age 49.15±3.28 years) were treated with either 10mg/day of Simvastatin (n=11), or Atorvastatin (n=9) for 4 months. Fourteen additional patients were recruited from the same clinic at the same hospital as a control group. The medication of these latter patients was unaltered for 4 months and the same parameters were measured as for the statin groups. Serum concentrations of zinc, copper, caeruloplasmin, selenium, glutathione peroxidase (GPx) and C-reactive protein (CRP) were measured together with their lipid profiles pre- and post-treatment. In addition to reducing serum total and low-density lipoprotein (LDL) cholesterol (p<0.0001), statin treatment was associated with a significant reduction in mean serum zinc (9%, p=0.03), copper (9%, p<0.01), caeruloplasmin (24%, p<0.05), and median CRP (45%, p<0.03). Similar changes were not observed in the control patients. No significant effects were observed for serum selenium, copper/caeruloplasmin ratio, or GPx (p>0.05) in either statin or control groups. These changes may be related to the known anti-inflammatory properties of the statin class of drugs.

OBJECTIVE:To investigate the factors that may affect antibody titres to heat shock proteins (Hsp)-60, -65 and -70, and serum C-reactive protein (CRP) concentrations in patients with dyslipidaemia and other features of the metabolic syndrome as defined by ATPIII criteria.MATERIAL AND METHODS:The study comprised 237 dyslipidaemia patients and 135 healthy individuals recruited from amongst university and hospital employees.RESULTS:Compared to the healthy individuals, the dyslipidaemic patients had higher antibody titres to Hsp-60 (p<0.01), Hsp-65 (p<0.001) and Hsp-70 (p<0.05), and higher serum CRP concentrations (p<0.001). The best-fitting multifactorial models revealed that known coronary risk factors explained little of the variation in Hsp antibody titres: 3 % for Hsp-60, 1 % for Hsp-65 and 4 % for Hsp-70 amongst the dyslipidaemic subjects. The corresponding values for the subgroup with the metabolic syndrome were 8 %, 3 % and 1 %, respectively. In contrast, the best-fitting model explained 13.5 % of the variation in serum CRP concentrations among the dyslipidaemic patients, obesity being a major determinant; and 14 % in the subgroup with metabolic syndrome.CONCLUSIONS:The higher antibody titres to Hsp-60, -65, and -70 in the dyslipidaemic patients may be related to a heightened state of immunoactivation associated with atherosclerosis in this group. Our data indicate that antibody titres to these Hsps are not associated with the classical coronary risk factors, although serum high sensitivity (hs)CRP concentrations were significantly related to obesity.

Background: We have investigated the association between serum copper, zinc and selenium concentrations, dietary intake, and demographic characteristics, including individual coronary risk factors, in healthy subjects. Methods: Serum copper, zinc and selenium were measured by atomic absorption spectrometry in 189 healthy subjects. Serum glutathione peroxidase and caeruloplasmin were also determined for each subject. A previously validated food frequency questionnaire was used to estimate the dietary trace element intake. Results: Male subjects had significantly lower serum copper ( P<0.001) and caeruloplasmin ( P<0.001), and higher serum zinc ( P<0.05) and zinc:copper ratio ( P<0.001) than female subjects. Significant differences were observed in serum copper and caeruloplasmin concentrations ( P<0.01) with age. Weak but significant associations between dietary trace elements and their serum concentrations were observed for zinc ( r=0.18, P=0.02), copper ( r=0.17, P=0.03) and selenium ( r=0.19, P=0.02). Obese subjects had significantly lower serum concentrations of zinc ( P<0.05). In multifactorial analysis, dietary zinc ( P<0.05), serum high-density lipoprotein-cholesterol (HDL-C) ( P<0.05), diastolic blood pressure ( P<0.05) and age ( P=0.05) emerged as major predictors of serum zinc concentrations. The corresponding predictors for serum copper were C-reactive protein (CRP) ( P<0.001), serum HDL-C ( P<0.001), gender ( P=0.01), physical activity levels ( P<0.05) and dietary copper ( P<0.05). Serum selenium concentrations were predicted by serum total cholesterol ( P<0.01), serum CRP concentrations ( P<0.05) and dietary selenium ( P<0.03). Conclusion: Serum copper, zinc and selenium concentrations are influenced by physiological conditions such as age, diet and gender. Their serum concentrations are also associated with coronary risk factors, including body mass index, levels of physical activity, serum HDL-C and CRP.

The objective was to test the hypothesis that dietary copper inhibits atherosclerosis by inducing superoxide dismutase (SOD) and potentiating nitric oxide (NO). New Zealand White rabbits were fed either a cholesterol diet (n = 8) or a cholesterol diet containing 0.02% copper acetate (n = 8) for 13 weeks. We found that the intimal area was significantly smaller in the animals supplemented with copper (P < 0.005), although integrated plasma cholesterol levels were not significantly different. This was associated with a significant increase in aortic copper content (P < 0.05), SOD activity (P < 0.05) and Cu/Zn SOD mRNA (P < 0.05) and a significant decrease in nitrotyrosine content (P < 0.05). Furthermore, there was a positive correlation between aortic copper content and SOD activity (P < 0.005, R(2) = 0.83) and a negative correlation between aortic superoxide dimutase activity and nitrotyrosine content (P < 0.005, R(2) = 0.93). In organ bath experiments, the relaxation of precontracted carotid artery rings to calcium ionophore was greater in animals supplemented with copper. No difference in response to sodium nitroprusside was observed. These data suggest that in the cholesterol-fed rabbit, copper supplements inhibit the progression of atherosclerosis by increasing SOD expression, thereby reducing the interaction of NO with superoxide, and hence potentiating NO-mediated pathways that may protect against atherosclerosis.

The recruitment of peripheral monocytes to the sub-endothelial space, their development into macrophages and subsequent proliferation are critical events during atherosclerosis. Receptors for epidermal growth factor (EGF) have been identified on cells of the myeloid lineage, but a role for them in atherogenesis has yet to be described. We have identified functional EGF receptors (EGFR, ErbB1/HER-1) on peripheral blood monocytes and monocyte-derived macrophages. Uniquely, these receptors were found to mediate both chemotaxis in monocytes and macrophages and proliferation in macrophages. EGFR mRNA was detected in atherosclerotic plaques, but not in morphologically normal aortae and EGFR receptor staining co-localised with macrophage staining in these plaques. The identification of receptors for EGF on peripheral blood monocytes, macrophages and atherosclerotic lesions, together with their transduction of two functionally important cellular events, heightens the potential importance of members of the EGF super-family in atherogenesis and other chronic inflammatory processes.

An immune response to heat shock protein (HSP)-60/65 has recently been implicated in atherogenesis. The aim of this study was to determine whether this effect may be mediated by impairment of endothelial function. Rabbits were injected with bacillus Calmette-Guerin (BCG) vaccine (n=12) or saline (n=12). A further injection of BCG or saline was administered after 2 weeks. After a further 2 weeks, animals were fed either a 0.25-1% cholesterol diet or a chow diet for 16 weeks. Blood cholesterol levels were maintained at 10-12mmol/l by altering the dietary cholesterol content. Plasma levels of anti-mycobacterial antibodies rose following BCG immunisation, but anti-HSP antibodies developed only in the BCG-immunised, cholesterol-fed rabbits. Aortic endothelium from cholesterol-fed, but not chow-fed, rabbits stained positively for HSP-60, independently of the immunisation protocol. Endothelial function was impaired in the BCG immunised, cholesterol-fed rabbits as measured by acetylcholine-mediated relaxation of isolated non-atherosclerotic carotid artery rings (P<0.05). This impairment was positively associated with the level of plasma anti-HSP-60 antibodies (P<0.01). These results suggest that BCG immunisation impairs endothelial responses, at least in part, by immune responses against mycobacterial and vascular HSP.

The evidence that oxidative lipid modification may be involved in the genesis of common diseases, such as atherosclerosis, is persuasive, but it was, until recently, conjecture based on in vitro findings, or investigation using experimental animal models. Recent clinical intervention studies in patients at high risk of cardiovascular events have been, at best, inconclusive. This has led to a general consensus that antioxidant supplements are of no value in the prevention of cardiovascular disease in subjects at high risk. However, epidemiological studies have demonstrated that the protective effects of antioxidant supplements, specifically vitamin E, were particularly evident amongst healthy subjects taking supplements. The picture is further clouded by the uncertain mechanism of lipoprotein modification within the artery wall, the possibility that some antioxidants may, under certain conditions, become pro-oxidants, the complex interactions between lipid- and water-soluble antioxidants, and the fact that free-radical-mediated events may only be important in the early stages of atherogenesis. Recent results also suggest that the biological efficacy of antioxidants, such as alpha-tocopherol, may be compromised by the conditions extant within the plaque. It is evidently important that the position on the benefits of antioxidants, whether in food or as supplements, in disease prevention is clarified.

Conference Abstract| January 01 2003 Inhibition of Platelet-Derived Growth Factor-Aa Reduces the Collagen Content of Aortic Lesions from Cholesterol-Fed Rabbits AC Dreux; AC Dreux 1Centre for Clinical Science & Measurement, School of Biomedical & Life Sciences, University of Surrey, Guildford, GU2 7XH Search for other works by this author on: This Site PubMed Google Scholar DJ Lamb; DJ Lamb 1Centre for Clinical Science & Measurement, School of Biomedical & Life Sciences, University of Surrey, Guildford, GU2 7XH Search for other works by this author on: This Site PubMed Google Scholar GAA Ferns GAA Ferns 1Centre for Clinical Science & Measurement, School of Biomedical & Life Sciences, University of Surrey, Guildford, GU2 7XH Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (2003) 104 (s48): 10P. https://doi.org/10.1042/cs104010Pa Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation AC Dreux, DJ Lamb, GAA Ferns; Inhibition of Platelet-Derived Growth Factor-Aa Reduces the Collagen Content of Aortic Lesions from Cholesterol-Fed Rabbits. Clin Sci (Lond) 1 January 2003; 104 (s48): 10P. doi: https://doi.org/10.1042/cs104010Pa Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 2003 The Biochemical Society and the Medical Research Society2003 Article PDF first page preview Close Modal You do not currently have access to this content.

Oxidised low density lipoprotein (LDL) may play a role in atherogenesis. We have investigated some of the mechanisms by which the thiol cysteine and the disulphide cystine can influence the oxidation of LDL by copper ions. Cysteine or cystine (100 μM) inhibited the oxidation of native LDL by copper in a simple phosphate buffer. One of the mechanisms by which cysteine (or more likely its oxidation products in the presence of copper) and cystine inhibited LDL oxidation was by decreasing the binding of copper to LDL (97% inhibition). Cysteine, but not cystine, rapidly reduced Cu2+ to Cu+. This may help to explain the antioxidant effect of cysteine as it may limit the amount of Cu2+ that is available to convert α-tocopherol in LDL into the prooxidant α-tocopherol radical. Cysteine (but not cystine) had a prooxidant effect, however, toward partially oxidised LDL in the presence of a low copper concentration, which may have been due to the rapid breakdown of lipid hydroperoxides in partially oxidised LDL by Cu+ generated by cysteine. To prove that cysteine can cause the rapid breakdown of lipid hydroperoxides in LDL, we enriched LDL with lipid hydroperoxides using an azo initiator in the absence of copper. Cysteine, but not cystine, increased the rate of lipid hydroperoxide decomposition to thiobarbituric acid-reactive substances (TBARS) in the presence of copper.

Atherosclerosis has long been recognised as having an inflammatory component, and this has a particularly important bearing on to its clinical complications as it may result in plaque instability. Results of recent epidemiological studies have reinforced the potential importance of this aspect of the disease. Positive associations have been reported between exposure to several specific pathogens, and future risk of coronary heart disease (CHD). Whilst it is possible that each individual organism contributes to this susceptibility by a different mechanism, it is more likely that one or more common mechanism(s) exist. One possible hypothesis is that an immune response mounted against antigens on pathogenic organisms cross-react with homologous host proteins in a form of ‘molecular mimicry’. A group of protein candidates that may be implicated in this process are the stress-induced proteins collectively known as heat shock proteins (HSP). HSPs are expressed and/or secreted by several pathogens, principally Chlamydia pneumoniae and Helicobacter pylori, but are also elaborated by mammalian vascular cells exposed to the stress associated with reperfusion injury or acute hypertension. The HSPs are also expressed by cells within atherosclerotic plaques. Serum titres of anti-HSP antibodies have been reported to be positively related to future risk of CHD. In addition, purified anti-HSP antibodies recognise and mediate the lysis of stressed human endothelial cells and macrophages in vitro. Furthermore, immunisation with HSP exacerbates atherosclerosis in experimental animal models. Some human vaccines, such as BCG, contain HSPs, hence although vaccination programmes are vital for maintaining ‘herd’ immunity and the prevention of serious infectious disease, they may leave a legacy of increased susceptibility to atherosclerosis. Development of HSP-free vaccines could satisfy the twin goals of protection from infection and reduced incidence of coronary disease.