Osteopontin levels are associated with cholesterol synthesis markers in mildly hypercholesterolaemic patients.

OBJECTIVE: Atherosclerotic lesions are characterized by an accumulation of inflammatory cells and lipids. Osteopontin (OPN) is a cell-binding phosphoprotein, and it seems to promote the development of atherosclerosis. The purpose of our study was to find out whether plasma levels of OPN are associated with cholesterol metabolites in plasma or tissues. METHODS AND RESULTS: Forty-three normal or mildly hypercholesterolaemic subjects, aged 31 to 69, were studied. The plasma level of OPN correlated negatively with muscle lathosterol (r = -0.52, P < 0.0001) and with the muscle lathosterol to muscle cholesterol ratio (r = -0.48, P = 0.001). Lathosterol concentrations in muscle (P = 0.003) and in relation to cholesterol (P = 0.005) were also significantly different among the OPN tertiles. OPN correlated negatively and significantly with muscle lathosterol in men (r = -0.58, P = 0.001, n = 29) but not in women (r = -0.21, P = 0.48, n = 14). Correspondingly, it also correlated negatively and significantly with the muscle lathosterol to muscle cholesterol ratio (r = -0.60, P = 0.001) in men but not in women (r = -0.13, P = 0.65). Plasma levels of OPN had a non-significant inverse correlation with plasma lathosterol and the plasma lathosterol to plasma cholesterol ratio. Plasma OPN concentrations were not related to plant sterols, cholesterol and 27-hydroxycholesterol. CONCLUSIONS: Tissue markers of cholesterol synthesis were related to plasma OPN, particularly in men. This suggests that there is interplay between OPN and cholesterol metabolism in human cells.

Plasma-soluble CD40 is related to cholesterol metabolism in patients with moderate hypercholesterolemia.

OBJECTIVES: CD40 is a marker of immunological activation and is expressed in the atherosclerotic lesions. We studied whether CD40 and cholesterol synthesis pathways are associated with each other. DESIGN: Forty-three subjects were randomly assigned to receive either simvastatin (n = 14), atorvastatin (n = 15), or placebo (n = 14) for eight weeks. Plasma samples were obtained before and at the end of the follow-up. sCD40 levels were measured in duplicate using an enzyme-linked immunosorbent assay. Cholesterol, its precursor lathosterol, the plant sterols campesterol and sitosterol as well as 27-hydroxycholesterol were quantified by gas-liquid chromatography-mass spectrometry. RESULTS: sCD40 was inversely correlated with the lathosterol to cholesterol ratio (r = - 0.47, p = 0.002), an indicator of cholesterol synthesis rate, as well as apolipoprotein A-I (r = - 0.38, p = 0.01) in addition to being directly correlated with 27-hydroxycholesterol (r = 0.40, p = 0.008). In multivariate linear regression analysis these three predictors explained 37% of the total variability of sCD40 levels. Simvastatin or atorvastatin treatment had no significant effect on sCD40 levels. CONCLUSION: These results indirectly suggest that sCD40 concentrations are related to cellular cholesterol levels. This may be a novel indication for the relationship between immunological processes and cholesterol metabolism.

Plasma asymmetric dimethylarginine (ADMA), nitrate and the indices of low-density lipoprotein oxidation.

BACKGROUND: Oxidative modification of low-density lipoprotein (LDL) is an important contributor to atherosclerosis. Also, oxidized LDL is suspected to cause accumulation of asymmetric dimethylarginine (ADMA), an endogenous competitive nitric oxide synthase inhibitor, which is suggested to be an independent risk factor for atherosclerosis. This study was performed to evaluate how plasma ADMA is related to plasma nitric oxide production, oxidized LDL and ex vivo susceptibility of LDL to oxidation in mildly hypercholesterolemic otherwise healthy subjects. METHODS: Plasma ADMA was determined using high performance liquid chromatography tandem mass spectrometry. LDL oxidation was estimated by the lag time and rate of copper-induced LDL oxidation. The nitric oxide production in plasma was estimated based on nitrate (NO(3)(-)) determination and plasma oxidized LDL was determined by a capture ELISA. RESULTS: Low ADMA was a significant determinant for high LDL oxidation rate and concentration of plasma ADMA was associated with nitrate levels. CONCLUSIONS: There may be an interplay between LDL fatty acid oxidation rate and plasma ADMA and nitrate. We hypothesize that plasma ADMA has a bivalent role: high ADMA may have a protective role in decelerating LDL fatty acid oxidation and also a risk factor for endothelial dysfunction by decreasing availability of nitric oxide.

Suppression of immune system genes by methylprednisolone in exacerbations of multiple sclerosis. Preliminary results.

Acute relapses of multiple sclerosis (MS) are treated with intravenous methylprednisolone (IVMP), which speeds recovery from exacerbation. It is known that IVMP suppresses the immunological activation which occurs during an acute attack of MS. However, the specific target genes affected by this therapy remain obscure. A cDNA microarray for 448 genes was used to identify the target genes in IVMP therapy. Total RNA was isolated from peripheral blood mononuclear cells derived from six MS patients immediately before and after completion of therapy. IVMP significantly reduced mRNA levels for T-cell-specific transcription factor 7 (p=0.02), T-cell-specific protein-tyrosine kinase (p=0.02), T-cell surface glycoprotein CD5 (p=0.05) and interferon-stimulated gene factor 3 gamma subunit (p=0.04). Significantly increased expression was found for eosinophil-derived neurotoxin (p=0.05). The suppression of expression of genes associated with T-cell differentiation and antigen-specific T-cell activation detected in this study may contribute to the beneficial effect of MP in relapses of MS.

Interleukin-1B genotype modulates the improvement of coronary artery reactivity by lipid-lowering therapy with pravastatin: a placebo-controlled positron emission tomography study in young healthy men.

A polymorphism at position -511 of interleukin-1B (IL-1B) gene promoter regulates IL-1B levels, immune and inflammatory responses and possible atherogenesis. We used positron emission tomography (PET) to study whether coronary reactivity or its response to pravastatin is related to this IL-1B polymorphism. The study comprised a randomized, double-blind, placebo-controlled trial with two treatment groups: (i) pravastatin (40 mg/day, n=14) and (ii) placebo (n=20) for 6 months (baseline mean cholesterol 5.5 +/- 0.8 mmol/l; age 35 +/- 4 years). Myocardial blood flow was measured by PET at rest and during adenosine infusion using 15O-labelled water. PET studies, lipid, IL-1beta and C-reactive protein analyses were performed at baseline and after 6 months of therapy. IL-1B genotype was determined by polymerase chain reaction. There were no differences between IL-1B allele 2 carriers (A2+) and non-carriers (A2-) in basal or adenosine-stimulated myocardial flow (ASMF), at baseline. Regarding the change in ASMF and coronary flow reserve, there was a significant IL-1B genotype-by-treatment group interaction (analysis of covariance, P=0.028 and P=0.002, respectively) during follow-up. In the pravastatin group, the ASMF increased by 18.0% in subjects with IL-1B A2- (n=7), but decreased by 2% in subjects with IL-1B A2+ (n=7). There were no significant changes from the baseline values in placebo recipients. After treatment, both genotype groups showed a similar decrease in serum total and low density lipoprotein cholesterol (P<0.0001 for both). In conclusion, coronary function improves after 6 months of pravastatin therapy in subjects with the IL-1B A2- allele but not in those with the IL-1B A2+ allele.