Cholesterol feeding activates macrophages to upregulate rat mesangial cell fibronectin production.

BACKGROUND: Cholesterol feeding has been shown to accelerate the development of glomerulosclerosis in many experimental renal diseases, possibly by promoting the infiltration of macrophages into the glomerulus. METHODS: In order to assess whether hyperlipidaemia could directly modulate macrophage function to promote glomerulosclerosis, confluent quiescent mesangial cells were exposed to resident (r) or elicited (e) macrophages, from either control (C) or cholesterol-fed (HC) rats or the conditioned media derived from the various macrophage preparations. RESULTS: All macrophage preparations stimulated mesangial cell fibronectin accumulation over medium alone, but eHC macrophages stimulated significantly greater fibronectin levels. Similarly, all macrophage conditioned media (MPCM) stimulated mesangial cell fibronectin production over medium alone and again the effect was greatest with MPCM derived from eHC macrophages. Proliferation studies using [(3)H]thymidine incorporation demonstrated that all conditioned media, with the exception of rC, stimulated significant mesangial cell proliferation over control levels. TGF-beta and PDGF, pro-fibrogenic growth factors known to be associated with macrophage infiltration, could not be detected in the MPCMs per se. However, they were detected in the culture supernatants of mesangial cells exposed to MPCMs and again secretion was greatest from mesangial cells exposed to eHC-MCPM. CONCLUSION: Monocytes are systemically activated by high serum cholesterol levels so that following maturation to macrophages they elaborate soluble factors that can stimulate mesangial cell fibronectin production, cell proliferation, and growth factor secretion. Hypercholesterolaemia may therefore accelerate glomerulosclerosis not only by increasing macrophage number, but also by upregulating the ability of macrophages to induce pro-sclerotic responses in glomerular mesangial cells.     

Turbulent blood flow plays an essential localizing role in the development of atherosclerotic lesions in experimentally induced hypercholesterolaemia in rats

Taking into account that atherosclerosis is a focal disease and high levels of plasma cholesterol are closely correlated with its pathogenesis, it is a challenge to explain how equal concentrations of cholesterol bathing the endothelium can produce local, rather than global, effects on arteries. The focal distribution of atherosclerotic lesions has been considered to be dependent, at least in part, on hydrodynamic factors. The present study was carried out to further test the hypothesis that these forces are an important localizing factor in rats feeding a hypercholesterolaemic diet and submitted to infra-diaphragmatic aortic constriction. These animals develop a normotensive prestenotic region with laminar blood flow that serves as control for a normotensive poststenotic region with turbulent blood flow. Our findings clearly demonstrated that the combination of turbulent blood flow and low wall shear stress (WSS) in the presence of hypercholesterolaemia and oxidative stress creates conditions to the formation of focally distributed incipient atherosclerotic lesions observed in the poststenotic segment. In contrast, only diffuse fatty streaks could be observed in the normotensive prestenotic segment with laminar blood flow and normal WSS in the presence of hypercholesterolaemia and oxidative stress. Although haemodynamic forces are not by themselves responsible for the pathogenesis of atherosclerosis, they prime the local vascular wall in which the lesion develop. Further studies are required to establish how haemodynamic forces are detected and transduced into chemical signalling by the cells of the artery wall and then converted into pathophysiologically relevant phenotypic changes.     

Low intestinal cholesterol absorption is associated with a reduced efficacy of phytosterol esters as hypolipemic agents in patients with metabolic syndrome

Background & aims

Phytosterols (PS) lower LDLc, but their effect on metabolic syndrome (MetS) remains unknown. We evaluated whether low-fat milk enriched with PS improves cardiovascular risk factors in these patients.

Methods

A randomised parallel trial employing 24 moderate-hypercholesterolaemic MetS patients and consisting of two 3-month intervention phases. After a 3-month healthy diet, patients were divided into two intervention groups: diet (n = 10) and diet + PS (n = 14) (2 g/day). A control group of 24 moderate-hypercholesterolaemic patients without MetS (matched in age and BMI) underwent the same procedure.

Results

Neither dietary intervention nor enrichment of PS induced any improvement in the serum lipoprotein profile of MetS patients. By contrast, in the non-MetS population, a healthy diet effectively reduced TC, LDLc, non-HDLc and Apo B-100, with further decreases in TC (6.9%), LDLc (10.5%), non-HDLc (10.3%), Apo B-100 (6.2%) and Apo B-100/ApoA-I ratio (11.6%) being observed when PS were administered. No differences in LDL diameter, hsCRP or homocysteine were detected in any of the groups after consuming PS. This supplementation produced a significant increase in PS levels only in the non-MetS population.

Conclusions

PS therapy appears to be of little value to MetS patients, likely due to its reduced intestinal cholesterol absorption. The efficacy of PS as hypocholesterolaemic agents is thus limited.     

Dietary mushroom (Pleurotus ostreatus) ameliorates atherogenic lipid in hypercholesterolaemic rats

1. The effects of edible oyster mushroom Pleurotus ostreatus on plasma and liver lipid profiles and on the plasma total anti-oxidant status were estimated in hyper- and normocholesterolaemic Long Evans rats. 2. The feeding of 5% powder of the fruiting bodies of P. ostreatus mushrooms to hypercholesterolaemic rats reduced their plasma total cholesterol by approximately 28%, low-density lipoprotein-cholesterol by approximately 55%, triglyceride by approximately 34%, non-esterified fatty acid by approximately 30% and total liver cholesterol levels by > 34%, with a concurrent increase in plasma high-density lipoprotein-cholesterol concentration of > 21%. However, these effects were not observed in mushroom-fed normocholesterolaemic rats. 3. Mushroom feeding significantly increased plasma fatty acid unsaturation in both normo- and hypercholesterolaemic rats. 4. Plasma total anti-oxidant status, as estimated by the oxidation of 2,2'-azino-bis-[3-ethylbenz-thiazoline-6-sulphonic-acid], was significantly decreased in mushroom-fed hypercholesterolaemic rats, concomitant with a decrease in plasma total cholesterol. 5. The present study suggests that 5% P. ostreatus supplementation provides health benefits, at least partially, by acting on the atherogenic lipid profile in the hypercholesterolaemic condition.     

Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia

The microsomal triglyceride transfer protein (MTP) inhibitor lomitapide is a licenced adjunct to a low-fat diet and other lipid-lowering medication, with or without low-density lipoprotein apheresis, for the treatment of adults with homozygous familial hypercholesterolaemia (HoFH). In a recently published phase 3 study, patients with HoFH received lomitapide in addition to maximally tolerated lipid-lowering therapy. Treatment with lomitapide resulted in a mean approximate 50% reduction in LDL-C levels after 26 weeks compared with baseline levels (p < 0.0001). This decrease in LDL-C was maintained at Weeks 56 and 78 (44% [p < 0.0001] and 38% [p = 0.0001], respectively). This paper offers clinical perspectives based on selected case histories of patients participating in the phase 3 lomitapide study. These cases provide illustrative examples of the efficacy of lomitapide, with or without apheresis, and show that the effective management of adverse effects can enable patients to remain on effective treatment.     

Increased formation of 8-iso-prostaglandin F(2alpha) is associated with altered bone metabolism and lower bone mass in hypercholesterolaemic subjects

OBJECTIVES: To investigate the relationship of 8-iso-prostaglandin (PG) F(2alpha) levels, a reliable marker of in vivo oxidative stress and lipid peroxidation, with bone mineral density (BMD), bone turnover markers, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) in hypercholesterolaemia. DESIGN: Cross-sectional study. SETTING: University hospital centre. METHODS: Serum 8-iso-PGF(2alpha) levels were measured in 173 hypercholesterolaemic subjects and in 152 age- and sex-matched normocholesterolaemic controls. Femoral neck and lumbar spine BMD, serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), OPG and RANKL levels, as well as urinary levels of C-terminal telopeptides of type I collagen (CTX-I), were also assessed. RESULTS: Hypercholesterolaemic subjects showed higher (P < 0.0001) serum 8-iso-PGF(2alpha) levels than controls. They also had decreased (P < 0.0001) femoral neck and lumbar spine BMD, and lower (P < 0.0001) serum BAP and OC levels. No significant differences between hypercholesterolaemic and control subjects were found when comparing urinary CTX-I levels, or serum OPG and RANKL levels. In multivariate linear regression analysis, serum 8-iso-PGF(2alpha) was the only negative predictor for femoral neck BMD and serum BAP and OC levels in hypercholesterolaemic subjects. No significant correlation (all P > 0.25) was present between serum 8-iso-PGF(2alpha) levels and urinary CTX-I levels, or serum OPG and RANKL levels, in hypercholesterolaemic subjects. CONCLUSIONS: We found an association between increased serum 8-iso-PGF(2alpha) levels and lower bone mass and reduced serum BAP and OC concentrations in hypercholesterolaemic subjects. These results would suggest a possible role for oxidative stress in the development of lower bone mass in hypercholesterolaemia.     

Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid‐lowering therapies

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)‐cholesterol. Standard lipid‐lowering drugs and LDL‐apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL‐apheresis and transplantation, but long‐term safety and efficacy data are lacking for all of these options.     

Low-density lipoprotein receptor gene mutation analysis and clinical correlation in Belgian hypercholesterolaemics

It is generally believed that patients with familial hypercholesterolaemia (FH) have a higher cardiovascular risk than hypercholesterolaemics without a defect in the low-density lipoprotein receptor (LDLR) gene. However, no conclusive evidence to support this view has yet been presented. We investigated this aspect in Belgian hyperlipidaemics as part of a comprehensive effort to determine the impact of FH in this population. DNA samples of 98 unrelated Belgian patients with a family history of autosomal dominant hypercholesterolaemia were screened for mutations in the LDLR gene, after exclusion of known mutations causing familial defective apolipoprotein B-100 (FDB). Eight of the 22 distinct LDLR gene mutations identified in 27 subjects have not previously been described in other populations. As expected, the mutation-positive patients had a significantly worse lipid profile than the mutation-negative subjects (p<0.05), but this did not correlate with clinical cardiovascular status. In conclusion, the presence of a mutation in the LDLR gene was not a reliable predictor of cardiovascular risk in the hyperlipidaemic subjects included in this study. However, it is possible that prolonged exposure to the high levels of LDL cholesterol in genetically proven FH patients will in future cause a higher incidence of coronary heart disease. Our data may reflect the genetic heterogeneity of inherited hypercholesterolaemia, recently shown to be caused by several major genes.     

Prevalence of familial hypercholesterolaemia in patients presenting with premature acute coronary syndrome

Central illustration. Prevalence of familial hypercholesterolaemia (FH) among young adults with myocardial infarction (MI) (n = 457) and in the general control population (CARVAR 92 cohort) (n = 9900), and cardiovascular risk factors associated with premature acute MI.

     

Heart rate and blood pressure variability and baroreflex sensitivity in hypercholesterolemia

Summary. To evaluate cardiovascular autonomic function in hypercholesterolaemia, we studied 16 age-matched pairs of healthy males with elevated serum cholesterol and normocholesterolaemic control subjects (altogether 37 men, aged 27–56 years). We used power spectral analysis to measure short-term heart rate and blood pressure variability, and the phenylephrine method to determine baroreceptor reflex sensitivity. The mean (SD) serum cholesterol concentration was 6.43 (1.22) among the hypercholesterolaemic subjects and 4.30 (0.44) mmol/1 among the control men (P<0.001). The respective low density lipoprotein (LDL) cholesterol concentrations were 4.44 (1.22) and 2.46 (0.38) mmol/1 (P<0.001). The total power (0.0-0.5 Hz) of heart rate and blood pressure variability did not differ between the groups, and neither did the high-frequency (0.15-0.5 Hz) and medium-frequency components (0.07-0.15 Hz). Mean (SD) baroreceptor reflex sensitivity was 18.1 (7.9) in hypercholesterolaemic and 19.4 (6.3) ms mmHg^-1 in normocholesterolaemic subjects (P=0.352). When all the subjects were analysed together, we observed a slight inverse trend between serum LDL cholesterol and baroreceptor reflex sensitivity (r= -0.235, P=0.161). In conclusion, hypercholesterolaemia does not alter autonomic neural regulation of the cardiovascular system as assessed by heart rate and blood pressure variability and baroreflex sensitivity.