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Department of Internal Medicine and Public Health, University of L’Aquila, 67100 Coppito-L’Aquila, Italy
Address all correspondence and requests for reprints to: Giovambattista Desideri, M.D., Department of Internal Medicine and Public Health, University of L’Aquila, Blocco 11-Via Vetoio, 67100 Coppito-L’Aquila, Italy. E-mail: giovambattista.desideri{at}cc.univaq.it.
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Abstract |
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(8-iso-PGF2) concentrations, as indexes of endothelial activation and lipid peroxidation, respectively, in 67 hypercholesterolemic patients compared with 32 normocholesterolemic subjects. Significant cholesterol reductions were achieved in hypercholesterolemic patients after 6 months under either simvastatin (40 mg/d) or bezafibrate (800 mg/d) treatment, given according to a randomized double-blind trial. Simvastatin but not bezafibrate simultaneously reduced soluble adhesin and total 8-iso-PGF2 concentrations also. Vitamin E supplementation (400 IU/d) further reduced indexes of endothelial activation and lipid peroxidation in simvastatin-treated patients and significantly reduced the above indexes in bezafibrate-treated patients. Changes in circulating soluble adhesion molecule levels were directly correlated with changes in total 8-iso-PGF2 concentrations in simvastatin-treated patients also receiving vitamin E supplementation. All together, our data demonstrated that hypercholesterolemia was combined with endothelial activation and lipid peroxidation, which were efficaciously counteracted by simvastatin but not bezafibrate treatment. Thus, a different vascular protection can be achieved by different lipid-lowering treatments. |
Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although poorly expressed by resting endothelium, endothelial adhesion molecules are rapidly up-regulated by several mechanical (4) and biochemical stimuli (1) acting on antioxidant-sensitive transcriptional regulatory mechanisms involved in nuclear translocation of transcriptional factor nuclear factor-
B (5). In this regard, lysophosphatidylcholine (6), a component of modified low-density lipoprotein (LDL), and oxidized LDL (7) have been reported to up-regulate endothelial adhesion molecules. Furthermore, a significant vascular cell adhesion molecule-1 (VCAM-1) and E-selectin up-regulation was present in atherosclerotic plaques from hyperlipidemic rabbits (8), whereas a cholesterol-rich diet up-regulated VCAM-1 in rabbit aortic macrovascular (9) as well intestinal microvascular endothelial cells within 1–2 wk (10).
Despite the above experimental findings, no definitive data are currently available on behavior of endothelial adhesion molecules in hypercholesterolemic patients. In particular, circulating soluble (s)E-selectin levels have been reported to be either higher (11, 12) or in the normal range (13, 14) in hypercholesterolemic patients. Similarly, conflicting data are also available on soluble intercellular adhesion molecule-1 (ICAM-1) levels which have been described as increased (11, 12, 13) as well as normal (14, 15) in hypercholesterolemia. Finally, previous reports (12, 14, 15) failed to find increased circulating sVCAM-1 levels in hypercholesterolemic patients, whereas we recently observed increased sVCAM-1 concentration directly correlated with LDL levels in isolated hypercholesterolemia (16).
In this study, we aimed to clarify the behavior of sICAM-1, sVCAM-1, and sE-selectin levels in hypercholesterolemic patients without other cardiovascular risk or confounding factors. Moreover, because hypercholesterolemia is combined to enhanced lipid peroxidation (17), which might affect endothelial adhesin expression (6, 7), we also evaluated plasma levels of 8-iso-prostaglandin F2 (8-iso-PGF2), a well-accepted index of lipid peroxidation in vivo (18), in our study population. Finally, because statins (19, 20) but not bezafibrate have been reported to exert antioxidant effects, we also evaluated the effects of simvastatin and bezafibrate treatment on endothelial adhesin and total 8-iso-PGF2 levels in hypercholesterolemic patients.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Thirty-two normocholesterolemic (serum LDL-cholesterol levels, <3.0 mmol·liter-1) healthy subjects were selected according to the above criteria and used as control group for baseline comparisons.
Treatment of hypercholesterolemic patients
Hypercholesterolemic patients were randomly, double-blindly assigned to four treatment groups over a period of 6 months. The first group (group I; n = 19) was treated with simvastatin (40 mg/d). The second group (group II; n = 17) received bezafibrate (800 mg/d). The third group (group III; n = 15) was treated with simvastatin (40 mg) plus vitamin E (400 IU/d). The fourth group (group IV; n = 16) received bezafibrate (800 mg) plus vitamin E (400 IU/d). Vitamin E was supplied as -tocopherol (Roche Molecular Biochemicals, Milan, Italy) capsules (one per day) that were ingested with meal. To reduce the possible influence of diet changes, patients were invited to not modify the diet assigned at the beginning of the study. No other drugs were administered during the study.
The treatment phase of the study was followed by skilled researchers of our staff, who were unaware of study design, results, and purpose.
Blood samplings
After 30 d on an AHA step I diet, both hypercholesterolemic patients and controls were invited to return in our outpatient unit, after 12 h at fast, at 0800 h. Then, blood samples for measurements of serum lipid, plasma sICAM-1, sVCAM-1, E-selectin, and total 8-iso-PGF2 concentrations were drawn from an antecubital vein, 1 h after an iv catheter was inserted and kept pervious by saline infusion (0.2 ml/min). Heparin was not used due to its influence on endothelial adhesion molecule expression (21). On the same occasions, transferrin, erythrocyte sedimentation rate, C-reactive protein (CRP), complement fractions C3 and C4, IL-6, and vitamin E levels were also taken. In hypercholesterolemic patients, the above parameters were repeated after 1, 3, 4, and 6 months under pharmacological treatment.
This study was approved by our institutional review committee. All subjects gave informed consent.
Laboratory measurements
Serum total cholesterol and cholesterol subfractions and routine hematochemical check including transferrin, erythrocyte sedimentation rate, CRP, and complement fractions C3 and C4 were assessed by routine test on the same morning of blood samplings. Serum total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglyceride levels were assessed by enzymatic methods (Boheringer Mannheim, Mannheim, Germany), in the case of HDL cholesterol after precipitation of LDL- and very low-density lipoprotein-cholesterol fractions by phosphotungstate. LDL-cholesterol levels were assessed by the Friedewald method (22). For sICAM-1, sVCAM-1, sE-selectin, total 8-iso-PGF2, and IL-6 measurements, plasma aliquots were stored at -80 C in polypropylene tubes immediately after centrifugation (15 min; 4 C; 3000 rpm) of blood samples. For each patient group, plasma sICAM-1, sVCAM-1, sE-selectin, and IL-6 concentrations were assessed in a single batch by the use of a monoclonal antibody-based ELISA method (R & D Systems, Minneapolis, MN). Total 8-iso-PGF2 levels were assessed by immunoenzymatic method (Assay Design, Inc., Ann Arbor, MI). The coefficients of variation were 4.9, 5.8, 3.9, and 3.6%, respectively, for measurements of sICAM-1, sVCAM-1, sE-selectin, and total 8-iso-PGF2 concentrations. Plasma vitamin E concentrations were measured by HPLC according to the well-established method of Lee et al. (23). Because the absolute vitamin E levels may depend on that of concurrent plasma lipids (24), plasma vitamin E levels were expressed both in absolute concentrations and as the ratio of vitamin E/(total cholesterol + triglycerides), as previously described (25).
Statistics
Data were stored by a common database and analyzed by software SPSS (SPSS, Inc., Chicago, IL) and Primit (McGraw-Hill, New York, NY). Differences among the examined groups were tested for significance by one-way ANOVA followed by the Bonferroni’s test. Paired Student’s t test was used to compare intragroup blood pressure levels and plasma concentrations of all checked variables before and after treatment. Changes of each variable on each treatment were tested for significance by the ANOVA for repeated measures followed by post hoc analysis. Linear regression and correlation were used to evaluate relationships between variables. Statistical significance was considered as a value of P < 0.05. Unless otherwise stated, all data are presented as mean ± SD.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Hypercholesterolemic patients (groups I–IV) and control subjects were matchable for sex, age, blood pressure levels, inflammation indexes, and acute-phase reactant proteins (Table 1
). According with the entry criteria, serum total cholesterol and LDL-cholesterol concentrations were higher in hypercholesterolemic patients (groups I–IV) than control subjects (Table 2). The other metabolic parameters were similar in all patient groups and controls (Table 2). Serum IL-6 levels were undetectable (i.e. <3 pg·ml-1) in hypercholesterolemic patients and controls. Absolute plasma vitamin E levels were significantly higher in hypercholesterolemic patients than control subjects, whereas plasma vitamin E concentrations adjusted for total lipids were similar in patients and controls (Table 1).
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levels were higher in hypercholesterolemic patients (groups I–IV) than control subjects (Table 1
). In pooled hypercholesterolemic patients, sVCAM-1 levels were directly correlated with LDL (r = 0.400; P < 0.0001), whereas they were inversely correlated with HDL cholesterol (r = -0.349; P = 0.004). In the same patients, direct correlations between circulating total 8-iso-PGF2 levels and LDL (r = 0.305; P = 0.012), sICAM-1 (r = 0.291; P = 0.017), sVCAM-1 (r = 0.267; P = 0.029), and sE-selectin (r = 0.256; P = 0.036) concentrations were also observed. Effects of cholesterol reduction on plasma soluble adhesion molecule concentrations
No changes of erythrocyte sedimentation rate, transferrin, and complement fractions C3 and C4 concentrations were observed in the four groups during the 6 months of pharmacological treatment. IL-6 levels remained undetectable (i.e. <3 pg·ml-1) after the various treatments. CRP showed a trend to decrease in patients receiving simvastatin (group I, from 2.1 ± 0.4 to 1.9 ± 0.3 mg·liter-1; P < 0.05) or simvastatin plus vitamin E (group III, from 1.8 ± 0.5 to 1.5 ± 0.4 mg·liter-1; P < 0.05).
Both simvastatin (group I) and bezafibrate (group II) treatment significantly reduced both total and LDL-cholesterol concentrations (Table 3). Simvastatin treatment was more effective than bezafibrate in reducing both total (-30.4 ± 5.0 vs. -15.7 ± 3.2% after 6-month treatment; P < 0.0001) and LDL-cholesterol concentrations (-37.2 ± 10.4 vs. -20.1 ± 1.9% after 6-month treatment; P < 0.0001).
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Plasma sICAM-1, sVCAM-1, sE-selectin, and total 8-iso-PGF2 levels significantly decreased during the 6 months of the simvastatin treatment period (Fig. 1). Peak decrements of plasma sICAM-1, sVCAM-1, and total 8-iso-PGF2 concentrations were achieved after 3 months, whereas the maximum decrement of plasma sE-selectin levels was observed after 6 months under simvastatin treatment. In contrast to simvastatin, bezafibrate treatment did not modify circulating sICAM-1, sVCAM-1, E-selectin, and total 8-iso-PGF2 levels (Fig. 1).
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concentrations in simvastatin-treated patients (group III; Fig. 1) and significantly reduced all of the tested variables in bezafibrate-treated patients (group IV; Fig. 1).
Changes in total 8-iso-PGF2 levels directly correlated with changes in sICAM-1 (Fig. 2A), sVCAM-1 (B), and sE-selectin (C) concentrations in simvastatin-treated hypercholesterolemic patients also receiving vitamin E supplementation (group III). A similar trend toward a direct correlation between changes in soluble adhesin levels and total 8-iso-PGF2 concentrations was evident also in patients receiving simvastatin alone (group I, sICAM-1, r = 0.454, P = 0.051; sVCAM-1, r = 0.439, P = 0.060; sE-selectin, r = 0.460, P = 0.048)
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In the current report, we described elevated circulating sICAM-1, sVCAM-1, and sE-selectin concentrations in nonatherosclerotic patients with elevated LDL-cholesterol but normal triglyceride levels. These data expanded on previous findings on circulating sE-selectin (11, 12), sICAM-1 (11, 12, 13), and sVCAM-1 (16) concentrations in hypercholesterolemic patients. By contrast, our report did not agree with previous studies (12, 14, 15) about plasma sVCAM-1 behavior in human hypercholesterolemia. Indeed, those studies (12, 14, 15) failed to find increased circulating levels of sVCAM-1 in hypercholesterolemic patients. Even more perplexing, a previous report by our group (26) showed only a slight elevation of plasma sVCAM-1 levels in essential hypertensive patients with mildly elevated cholesterol and triglyceride levels. However, a number of influential factors such as hypertriglyceridemia (12, 26), previous pharmacological treatments (12), different dietary habits due to ethnicity (14), and hypertension (26) might have affected plasma sVCAM-1 levels and led to the lack of its significant increase in such patients. Furthermore, it is interesting to note that Blann et al. (15) found circulating sVCAM-1 concentrations in normal subjects close to those observed in our hypercholesterolemic population.
As far as mechanism leading to endothelial adhesin up-regulation in our hypercholesterolemic patients, in vitro data clearly demonstrated that lysophosphatidylcholine (6), a component of modified LDL, and oxidized LDL (7) stimulated ICAM-1, VCAM-1, and E-selectin expression by endothelial cells. In this regard, our hypercholesterolemic patients showed elevated plasma total 8-iso-PGF2 levels, a well-accepted index of lipid peroxidation in vivo (18). Because total 8-iso-PGF2a concentrations were directly correlated with soluble adhesin levels, it was intriguing to speculate that hypercholesterolemia-related (17) enhanced lipid peroxidation could have affected endothelial molecule expression in our hypercholesterolemic patients.
The most interesting finding of our study was the significant decrement of plasma sICAM-1, sVCAM-1, and sE-selectin concentrations observed after simvastatin treatment in hypercholesterolemic patients. These findings appeared to be particularly interesting, because bezafibrate therapy failed to reduce circulating endothelial adhesin levels despite a significant reduction of both total and LDL-cholesterol concentrations. In this context, simvastatin was more effective than bezafibrate treatment in reducing both total and LDL-cholesterol concentrations. Thus, the lack of the evidence of endothelial protection in bezafibrate-treated patients could have been due to the smaller cholesterol reduction achieved in this treatment group. Although reasonable, this explanation was not supported by the evidence of a correlation between changes in soluble adhesin levels and changes in lipid concentrations in both simvastatin- and bezafibrate-treated patients. In addition, it was interesting to observe that 3 months of simvastatin treatment reduced LDL-cholesterol concentrations to a level (-19.7 ± 3.7%; P < 0.0001 vs. baseline) that was close to that observed after 6 months of bezafibrate treatment (-20.1 ± 1.9%; P < 0.0001 vs. baseline). Despite this, there was no reduction of sICAM-1, sVCAM-1, and sE-selectin concentrations during the whole bezafibrate treatment period. By contrast, a significant reduction of soluble adhesion molecule levels was already evident starting from the first month under simvastatin therapy. Thus, our data clearly demonstrated that drug-induced cholesterol lowering is not necessarily associated with a reduction of endothelial activation in hypercholesterolemic patients. Interestingly, simvastatin treatment lowered plasma adhesin concentrations below the control mean levels. In this context, we already demonstrated that vitamin E supplementation was able to reduce sVCAM-1 concentrations below the control values in hypercholesterolemic patients (16). Even more interesting, prolonged, low-dose antioxidant supplementation lowered plasma sICAM-1 levels also in normal subjects, i.e. in the presence of not-increased soluble adhesin concentrations (27). These findings clearly demonstrated that a lower threshold of endothelial activation does not exist. By contrast, circulating soluble adhesion molecule concentrations simply reflect a continuous balance between activating and protective factors acting on the endothelium. In this regard, simvastatin has all the pharmacological potentialities to counteract endothelial activation by reducing oxidative stress (19, 20), which play a pivotal role in endothelial activation (6, 7), and altering endothelial response to different stimuli (28, 29, 30). Thus, the reduction of adhesin values below the mean control values observed in simvastatin-treated patients likely reflects the efficacy of simvastatin in counteracting endothelial activation.
In contrast to our evidence, Hackman et al. (12) described unaffected plasma adhesin concentrations in hypercholesterolemic patients after atorvastatin treatment. In our opinion, discrepancies with our findings simply reflect the different study conditions, i.e. number of treated patients, and different potency and pharmacokinetic and chemical structure of HMGCoA inhibitors (31). Even more perplexing, a recent report by Sardo et al. (13) failed to find significant changes in both sE-selectin and sICAM-1 after simvastatin treatment. Interestingly, in this report, hypercholesterolemic patients received 20 mg/d simvastatin over a period of 6 months. Because we observed a significant reduction of circulating sICAM-1, sVCAM-1, and sE-selectin levels in hypercholesterolemic patients receiving the same drug for the same period but at higher dose (i.e. 40 mg/d simvastatin), it was intriguing to speculate that endothelial protective effects exerted by simvastatin against endothelial activation in hypercholesterolemic patients could be dose dependent. On the other hand, methodological issues related to the enzyme-linked immunoassays used to evaluate adhesin values unlikely contributed to the discrepancies between our findings and previous reports (12, 13). Indeed, assays used to assess all of the tested variables showed low coefficients of variation, which were within the range indicated by the suppliers. Neither should spontaneous adhesion level variability be taken into account to explain discrepancies between our data and previous reports, because soluble adhesin concentrations have been reported to be stable during the time in untreated hypercholesterolemic patients (16).
With regard to the mechanism leading to the reduction of soluble endothelial adhesion molecules observed after simvastatin treatment, it was interesting to observe a significant reduction of total 8-iso-PGF2 levels, i.e. a well-accepted index of oxidative stress (18), after simvastatin but not bezafibrate treatment. According to our findings, De Caterina et al. (19) recently found a drastic reduction of lipid peroxidation products after simvastatin treatment in hypercholesterolemic patients. In our study, changes in total 8-iso-PGF2 concentrations and changes in sICAM-1, sVCAM-1, and sE-selectin levels observed after simvastatin treatment showed a trend toward a direct correlation, which achieved statistical significance in simvastatin-treated patients also receiving vitamin E supplementation. Because oxidized lipids can activate endothelial cells (6, 7), the differences observed in endothelial cell activation in response to simvastatin could be, at least in part, in response to reducing levels of oxidized lipids. According to this, the reduction of circulating adhesin levels induced by simvastatin treatment was close to that induced by the antioxidant vitamin E supplementation in bezafibrate-treated patients. Although this explanation was the most likely, the weak correlation between endothelial activation and oxidation indexes observed in hypercholesterolemic patients receiving simvastatin alone did not definitively support our data interpretation. In addition, statins have been demonstrated to have direct protective effects on endothelial cells, altering their response to various stimuli (28, 29). In this context, Li et al. (30) recently demonstrated that statins reduced oxidized LDL-induced VCAM-1 and ICAM-1 production by cultured endothelial cells obtained by human coronary arteries. Thus, the direct effects of statins on endothelial cell activation, which have been already demonstrated in vitro to be independent on levels of lipoprotein-associated lipid peroxides (28, 29, 30), should be considered also in vivo to explain the endothelial protection exerted by simvastatin.
Vitamin E supplementation further reduced soluble adhesion molecule and total 8-iso-PGF2 concentrations in simvastatin-treated patients. These data suggested that vitamin E could cooperate with simvastatin in counteracting endothelial activation in hypercholesterolemic patients. In contrast to our evidence, De Caterina et al. (19) failed to find an additional effect of vitamin E on simvastatin-related reduction of lipid peroxidation in hypercholesterolemic patients. However, as the authors (19) correctly focused on, vitamin E could exert variable antioxidant effects in different patients characterized by variable degree of lipid peroxidation. Indeed, the basal rate of lipid peroxidation represents the major determinant of the response to vitamin E supplementation (32). In this context, it was interesting to observe that we carefully excluded from our study clinical conditions that have been reported to be associated with increased oxidative stress such as hypertension (33), diabetes (34), or smoking (35). Thus, discrepancies with the report by De Caterina et al. (19) could simply reflect the different selection criteria. The same reasons could also explain the lack of additional effects of vitamin E supplementation on simvastatin-related reduction of cardiovascular events (36).
With regard to possible study limitations, hypercholesterolemic patients were not treated with placebo for obvious ethical concerns. Thus, we cannot completely exclude that changes in dietary habits could have affected, at least in part, markers of endothelial activation and lipid peroxidation. In this context, a previous report by our group (16) failed to find significant changes in sVCAM-1 levels in isolated hypercholesterolemia after 8 wk under an AHA step I diet. In addition, in the current study, all four patient groups were assigned to the same diet, i.e. AHA step I diet, at the beginning of the study and were invited to not modify the diet during the whole treatment period. Thus, it is extremely unlikely that diet could have affected our findings.
To summarize, the present study provided clear evidence that 1) circulating levels of endothelial adhesion molecules, i.e. a well-accepted index of endothelial activation, were increased in isolated hypercholesterolemia; 2) enhanced lipid peroxidation likely represented the mechanism responsible for such endothelial activation; 3) simvastatin and bezafibrate treatments significantly reduced cholesterol concentrations, but only simvastatin treatment decreased endothelial adhesin concentrations; and 4) simvastatin-related changes in lipid peroxidation likely play a pivotal role in the endothelial protection exerted by simvastatin. However, direct protective effects of simvastatin on endothelial activation already demonstrated in vitro (28, 29, 30) should be considered also in vivo. All together, these findings clearly demonstrated that cholesterol reduction is not necessarily accompanied by a decrement of endothelial activation and lipid peroxidation. As a consequence, a different vascular protection can be achieved by different lipid-lowering treatments in hypercholesterolemic patients.
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Footnotes |
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, 8-iso-prostaglandin F2; LDL, low-density lipoprotein; s, soluble; VCAM-1, vascular cell adhesion molecule-1. Received April 24, 2003.
Accepted August 14, 2003.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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B and cytokine-inducible enhancers. FASEB J 9:899–909
is increased in hypercholesterolemia. Arterioscler Thromb Vasc Biol 17:3230–3235-tocopherol therapy counteracts intercellular cell adhesion molecule-1 activation. Clin Chim Acta 320:5–9[CrossRef][Medline]
and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 99:224–229This article has been cited by other articles:
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A. Tenenbaum, E. Z. Fisman, and M. Motro Bezafibrate and Simvastatin: Different Beneficial Effects for Different Therapeutic Aims J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1978 - 1978. [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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), bezafibrate (group II; 
), simvastatin plus vitamin E (group III;
), and bezafibrate plus vitamin E (group IV;
). a, P < 0.0001 vs. group II; b, P < 0.003 or less vs. groups I and IV; c, P < 0.04 or less vs. 3 months; d, P < 0.02 vs. group I; e, P < 0.01 or less vs. groups I and IV; f, P < 0.004 or less vs. groups I and IV; g, P < 0.0006 or less vs. groups I and IV.